1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors

ABSTRACT

The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) 
                         
wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/282,663, filed Dec. 9, 2009, which is the National Stage Entry ofPCT/EP2007/052442, filed Mar. 15, 2007, which claims priority to (EP)Application No. 06111215.7, filed Mar. 15, 2006, and to (EP) ApplicationNo. 07103654.5, filed Mar. 7, 2007, each of which are herebyincorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to novel compounds, in particular novel1,4-disubstituted 3-cyano-pyridone-derivatives that are positiveallosteric modulators of metabotropic receptors-subtype 2 (“mGluR2”)which are useful for the treatment or prevention of neurological andpsychiatric disorders associated with glutamate dysfunction and diseasesin which the mGluR2 subtype of metabotropic receptors is involved. Theinvention is also directed to the pharmaceutical compositions, theprocesses to prepare such compounds and compositions and the use of suchcompounds for the prevention and treatment of such diseases in whichmGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino-acid transmitter in the mammalian centralnervous system (CNS). Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation oftonotropic glutamate receptors channels (iGluRs), the NMDA, AMPA andkainate receptors which are responsible for fast excitatory transmission(Nakanishi et al., (1998) Brain Res Brain Res Rev., 26:230-235).

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

The mGluRs are seven-transmembrane G protein-coupled receptors (GPCRs)belonging to family 3 of GPCRs along with the calcium-sensing, GABAb,and pheromone receptors.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signalling pathways.

The mGluR family is composed of eight members. They are classified intothree groups (group I comprising mGluR1 and mGluR5; group II comprisingmGluR2 and mGluR3; group III comprising mGluR4, mGluR6, mGluR7, andmGluR8) according to sequence homology, pharmacological profile, andnature of intracellular signalling cascades activated (Schoepp et al.(1999) Neuropharmacology, 38:1431-76).

Among mGluR members, the mGluR2 subtype is negatively coupled toadenylate cyclase via activation of Gαi-protein, and its activationleads to inhibition of glutamate release in the synapse (Cartmell &Schoepp (2000) J Neurochem 75:889-907). In the CNS, mGluR2 receptors areabundant mainly throughout cortex, thalamic regions, accessory olfactorybulb, hippocampus, amygdala, caudate-putamen and nucleus accumbens(Ohishi et al. (1998) Neurosci Res 30:65-82).

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders (Levine et al. (2002) Neuropharmacology 43: 294;Holden (2003) Science 300:1866-68; Grillon et al. (2003)Psychopharmacology 168:446-54; Kellner et al. (2005) Psychopharmacology179: 310-15). In addition, activating mGluR2 in various animal modelswas shown to be efficacious, thus representing a potential noveltherapeutic approach for the treatment of schizophrenia (reviewed inSchoepp & Marek (2002) Curr Drug Targets. 1:215-25), epilepsy (reviewedin Moldrich et al. (2003) Eur J Pharmacol. 476:3-16), migraine (Johnsonet al. (2002) Neuropharmacology 43:291), addiction/drug dependence(Helton et al. (1997) J Pharmacol Exp Ther 284: 651-660), Parkinson'sdisease (Bradley et al (2000) J Neurosci. 20(9):3085-94), pain (Simmonset al. (2002) Pharmacol Biochem Behav 73:419-27), sleep disorders(Feinberg et al. (2002) Pharmacol Biochem Behav 73:467-74) andHuntington's disease (Schiefer et al. (2004) Brain Res 1019:246-54).

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogs of glutamate (Schoepp et al. (1999)Neuropharmacology, 38:1431-76).

A new avenue for developing selective compounds acting at mGluRs is toidentify molecules that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. This typeof molecule has been discovered for several mGluRs (reviewed in Mutel(2002) Expert Opin. Ther. Patents 12:1-8). In particular molecules havebeen described as mGluR2 positive allosteric modulators (Johnson M P etal. (2003) J Med Chem. 46:3189-92; Pinkerton et al. (2004) J Med Chem.47:4595-9).

WO2004/092135 (NPS & Astra Zeneca), WO2004/018386, WO2006/014918 andWO2006/015158 (Merck) and WO2001/56990 (Eli Lilly) describe respectivelyphenyl sulfonamide, acetophenone, indanone and pyridylmethyl sulfonamidederivatives as mGluR2 positive allosteric modulators. However, none ofthe specifically disclosed compounds are structurally related to thecompounds of the invention.

It was demonstrated that such molecules do not activate the receptor bythemselves (Johnson M P et al. (2003) J Med Chem. 46:3189-92;Schaffhauser et al. (2003) Mol Pharmacol. 64:798-810). Rather, theyenable the receptor to produce a maximal response to a concentration ofglutamate which by itself induces a minimal response. Mutationalanalysis have demonstrated unequivocally that the binding of mGluR2positive allosteric modulators does not occur at the orthosteric site,but instead at an allosteric site situated within the seventransmembrane region of the receptor (Schaffhauser et al. (2003) MolPharmacol. 64:798-810).

Animal data are suggesting that positive allosteric modulators of mGluR2have the same effects in anxiety and psychosis models as those obtainedwith orthosteric agonists. Allosteric modulators of mGluR2 were shown tobe active in fear-potentiated startle (Johnson et al. (2003) J Med Chem.46:3189-92; Johnson et al. (2005) Psychopharmacology 179:271-83), and instress-induced hyperthermia (Johnson et al. (2005) Psychopharmacology179:271-83) models of anxiety. Furthermore, such compounds were shown tobe active in reversal of ketamine- (Govek et al. (2005) Bioorg Med ChemLett 15(18):4068-72) or amphetamine- (Galici et al. (2005) J Pharm ExpTher 315(3), 1181-1187) induced hyperlocomotion, and in reversal ofamphetamine-induced disruption of prepulse inhibition of the acousticstartle effect (Galici et al. (2005) J Pharm Exp Ther 315(3), 1181-1187)models of schizophrenia.

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 (Johnson et al. (2004)Biochem Soc Trans 32:881-87) or DCG-IV (Poisik et al. (2005)Neuropharmacology 49:57-69). These data provide evidence for yet anothernovel therapeutic approach to treat above mentioned neurologicaldiseases involving mGluR2, which would use a combination of a positiveallosteric modulator of mGluR2 together with an orthosteric agonist ofmGluR2.

DESCRIPTION OF THE INVENTION

The invention relates to compounds having metabotropic glutamatereceptor 2 modulator activity. In its most general compound aspect, thepresent invention provides a compound according to general Formula (I),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof, an N-oxide form thereof or aquaternary ammonium salt thereof, wherein

-   V¹ is selected from the group of a covalent bond and a bivalent    saturated or unsaturated, straight or branched hydrocarbon radical    having from 1 to 6 carbon atoms;-   M¹ is selected from the group of hydrogen; cycloC₃₋₇alkyl; aryl;    alkylcarbonyl; alkyloxy; aryloxy; arylalkyloxy; arylcarbonyl;    hexahydrothiopyranyl; and Het¹;-   L is selected from the group of a covalent bond; —O—; —OCH₂—;    —OCH₂CH₂—; —OCH₂CH₂O—; —OCH₂CH₂OCH₂—; —S—; —NR⁷—; —NR⁷CH₂—; —NR⁷    cycloC₃₋₇; —NR⁷CH₂CH₂—; —OCH₂CH₂N(R⁷)CH₂—; —CH₂—; —CH₂CH₂—;    —CH₂CH₂CH₂; —C≡C—; —C═O—; and —C(R⁸)═C(R⁹)—; wherein each of R⁷,    independently of each other, is selected from the group of hydrogen    and C₁₋₃alkyl; and wherein R⁸ and R⁹, independently of each other,    are selected from the group of hydrogen, halo and C₁₋₃alkyl;-   R² and R³ are each independently of each other hydrogen, halo or    alkyl;-   A is Het² or phenyl, wherein each radical is optionally substituted    with n radicals R⁴, wherein n is an integer equal to zero, 1, 2 or    3;-   R⁴ is selected from the group of halo; cyano; hydroxy; oxo; formyl;    ethanoyl; carboxyl; nitro; thio; alkyl; alkyloxy; alkyloxyalkyl;    alkyloxycarbonyl; alkyloxycarbonylalkyl; alkylcarbonyl;    alkylcarbonyloxy; alkylcarbonylalkyloxy; polyhaloC₁₋₃alkyl;    polyhaloC₁₋₃alkyloxy; polyhaloC₁₋₃alkylthio; alkylthio;    alkylsulfonyl; Het³; Het³-alkyl; Het³-oxy; Het³-oxyalkyl;    Het³-alkyloxy; Het³-oxyalkyloxy; Het³-carbonyl; Het³-carbonylalkyl;    Het³-thio; Het³-thioalkyl; Het³-sulfonyl; aryl; arylalkyl; aryloxy;    aryloxyalkyl; arylalkyloxy; arylalkenyl; arylcarbonylalkyl;    arylthioalkyl; arylsulfonyl; —NR^(a)R^(b); alkyl-NR^(a)R^(b);    O-alkyl-NR^(a)R^(b); —C(═O)—NR^(a)R^(b); —C(═O)-alkyl-NR^(a)R^(b);    and O-alkyl-C(═O)—NR^(a)R^(b); wherein R^(a) and R^(b) are selected    from the group of hydrogen, alkyl, alkylcarbonyl, arylalkyl,    alkyloxyalkyl, Het³, Het³alkyl, alkylsulfonyl, alkyl-NR^(c)R^(d) and    C(═O)alkyl-NR^(c)R^(d), wherein R^(c) and R^(d) are selected from    the group of hydrogen, alkyl and alkylcarbonyl;    -   or two radicals R⁴ may be combined to form a bivalent radical        —X¹—C₁₋₆—X²— wherein C₁₋₆ is a saturated or unsaturated,        straight or branched hydrocarbon radical having 1 to 6 carbon        atoms and X¹ and X² are each independently C, O or NH; wherein        the bivalent radical is optionally substituted with one or more        radicals selected from the group of halo, polyhaloC₁₋₃alkyl,        cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl and        ethanoyl;-   Het¹ is selected from the group of tetrahydropyranyl and pyridinyl;    wherein each radical is optionally substituted with 1, 2 or 3    substituents, each independently from each other, selected from the    group of halo, C₁₋₃alkyl, polyhaloC₁₋₃alkyl, polyhaloC₁₋₃alkyloxy,    cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl,    and C₁₋₃alkyloxy;-   Het² is selected from the group of piperazinyl; piperidinyl;    thienyl; furanyl; 1H-indazolyl; 1H-benzimidazolyl;    1,2,3,4-tetrahydro-isoquinolinyl; 2,5-diaza-bicyclo[2.2.1]heptyl;    pyrrolidinyl; azetidinyl; 2,7-diaza-spiro[3.5]-nonyl; pyridinyl;    pyrazolyl; indolinyl; 1H-indolyl; 1 JH-indazolyl; benzomorpholinyl;    thiazolyl; 1,2,3,4-tetrahydroquinolinyl; 3,9-diazaspiro[5.5]undecyl;    1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinyl;    1,2,3,4,4a,10a-hexahydrobenzo[5,6][1,4]dioxino[2,3-c]pyridinyl;    2,3,4,9-tetrahydro-1H-indeno[2,1-c]-pyridinyl;    2,3,4,9-tetrahydro-1H-β-carbolinyl;    1,2,3,4-tetrahydro-benzo[4,5]-furo[2,3-c]pyridinyl;    1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridinyl; [1,4]diazepyl;    isoxazolyl; indanyl; and indolyl;-   Het³ is selected from the group of pyridinyl; pyrimidinyl;    pyridazilyl; pyrazinyl; piperidinyl; pyrrolyl; pyrrolidinyl;    piperazinyl; triazolyl; tetrazolyl; indolyl; thienyl; furanyl;    tetrahydropyranyl; tetrahydro-thiopyran-1,1-dioxide; thiazolyl;    thiadiazolyl; isothiazolyl; oxazolyl; morpholinyl; oxadiazolyl;    isoxazolyl; imidazolyl; pyrazolyl; benzoimidazolyl; benzoxazolyl;    benzothienyl; benzothiazolyl; benzofuranyl; benzomorpholinyl;    1,2,3,4-tetrahydro-isoquinolinyl; thionaphtyl; indolyl; indolinyl;    quinolyl; isoquinolyl; quinoxalyl; phthalazyl; benzo[1,3]dioxyl; and    quinazolyl; wherein each radical is optionally substituted with 1, 2    or 3 substituents, each independently from each other, selected from    the group of halo, C₁₋₆alkyl, polyhaloC₁₋₃alkyl, cyano, hydroxy,    amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, phenyl,    pyrrolidinyl, piperidinyl, pyridinyl, morpholinyl, mono- and    di(alkyl)amino, and C₁₋₃alkyloxy; aryl is naphthyl, phenyl, or    biphenyl; wherein each radical is optionally substituted with 1, 2    or 3 substituents, each independently from each other selected from    the group of halo, C₁₋₃alkyl, polyhaloC₁₋₃alkyl,    polyhaloC₁₋₃alkyloxy, cyano, hydroxy, amino, oxo, carboxyl, nitro,    thio, formyl, ethanoyl, ethyloxycarbonyl, and C₁₋₃alkyloxy;-   alkyl is a saturated, straight or branched hydrocarbon radical    having from 1 to 6 carbon atoms; or is a saturated, cyclic    hydrocarbon radical having from 3 to 7 carbon atoms; or is saturated    hydrocarbon radical from 4 to 12 carbonatoms, comprising at least    one saturated, straight or branched hydrocarbon radical having from    1 to 6 carbon atoms and at least one saturated, cyclic hydrocarbon    radical having from 3 to 7 carbon atoms; wherein each carbon atom    may optionally be substituted with one or more radicals selected    from the group of halo, polyhaloC₁₋₃alkyl, cyano, hydroxy, amino,    oxo, carboxyl, nitro, thio, formyl, ethanoyl, carbamoyl, phenyl, and    a bivalent radical —OCH₂CH₂O—; and-   alkenyl is alkyl, additionally containing one or more double bonds.

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof, an N-oxide form thereof or aquaternary ammonium salt thereof.

The invention also relates to the use of a compound according to theinvention as a medicament and for the preparation of a medicament forthe prevention and/or treatment of a condition in a mammal, including ahuman, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of mGluR2 positive allosteric modulators.

In particular, the invention relates to the use of a compound accordingto the invention for the preparation of a medicament for treating, orpreventing, ameliorating, controlling or reducing the risk of variousneurological and psychiatric disorders associated with glutamatedysfunction in a mammal, including a human, the treatment or preventionof which is affected or facilitated by the neuromodulatory effect ofmGluR2 positive allosteric modulators.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein V¹ is selectedfrom the group of a covalent bond, —CH₂—; —CH₂—CH₂—; —CH₂—CH₂—CH₂—;—CH₂—CH═CH—; —CH₂—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃)—CH₂—;—CH(CH₃)—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃—)CH₂—CH₂—; and —CH₂—CH₂—CH(CH₃)—CH₂—.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein M¹ is selectedfrom the group of hydrogen; cycloC₃₋₇alkyl; phenyl; biphenyl; phenyloxy;benzyloxy; furanyl; and pyridinyl; wherein M¹ is optionally substitutedwith one or more radicals selected from the group of halo; C₁₋₃alkyl;polyhaloC₁₋₃alkyl; polyhaloC₁₋₃alkyloxy; cyano; hydroxy; amino; oxo;carboxyl; nitro; thio; formyl; ethanoyl; and C₁₋₃alkyloxy.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein M¹ is selectedfrom the group of hydrogen; cycloC₃₋₇alkyl; phenyl; biphenyl; phenyloxy;benzyloxy; furanyl, and pyridinyl; wherein any one of said radicals isoptionally substituted with one or more radicals selected from the groupof halo; C₁₋₃alkyl; polyhaloC₁₋₃alkyl; polyhaloC₁₋₃alkyloxy; andC₁₋₃alkyloxy.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein V¹-M¹ is selectedfrom the group of —CH₂—CH₂—CH₂—CH₃; —CH₂—CH(CH₃)—CH₃;—CH(CH₃)—CH₂—CH₂—CH₃; —CH₂—CH(CH₃—)CH₂—CH₃; —CH₂—CH₂—CH(CH₃)—CH₃; or V¹is selected from the group of covalent bond; —CH₂—; —CH₂—CH₂—;—CH₂—CH₂—CH₂—; and —CH₂—CH═CH—; and M¹ is selected from the group ofcyclopropyl; cyclopentyl; cyclohexyl; phenyl; biphenyl; phenyloxy;benzyloxy; furanyl; and pyridinyl; wherein each radical M¹ is optionallysubstituted with one or more radicals selected from the group of halo;C₁₋₃alkyl; polyhaloC₁₋₃alkyl; polyhaloC₁₋₃alkyloxy; and C₁₋₃alkyloxy. Ina particular embodiment, V¹-M¹ is —CH₂—CH₂—CH₂—CH₃.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein R² and R³ areeach independently hydrogen, chloro, fluoro or methyl. In one particularembodiment, R² and R³ are each independently hydrogen or methyl. Inanother particular embodiment, R² and R³ are each hydrogen. In anotherparticular embodiment, R² is methyl and R³ is hydrogen.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein L is selectedfrom the group of a covalent bond; —O—; —OCH₂—; —OCH₂CH₂—; —OCH₂CH₂O—;—OCH₂CH₂OCH₂—; —NR⁷—; —NR⁷CH₂—; —NR⁷cycloC₃₋₇; —OCH₂CH₂N(R⁷)CH₂—;—CH₂CH₂—; —C≡C—; —C═O—; and —CH═CH—; wherein each of R⁷, independentlyof each other, is selected from the group of hydrogen and C₁₋₃alkyl.

In another embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein A is selectedfrom the group of phenyl, piperazinyl, and piperidinyl; wherein each ofsaid radicals is optionally substituted with n radicals R⁴, wherein n isan integer equal to zero, 1, 2 or 3. In one particular embodiment, n isequal to zero or 1. In another particular embodiment, n is equal to 1.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein R⁴ is selectedfrom the group of halo; cyano; hydroxy; ethanoyl; alkyl; alkyloxy;alkyloxyalkyl; alkyloxycarbonyl; alkyloxycarbonylalkyl; alkylcarbonyl;alkylcarbonyloxy; alkylcarbonylalkyloxy; polyhaloC₁₋₃alkyl;polyhaloC₁₋₃-alkyloxy; polyhaloC₁₋₃alkylthio; alkylthio; alkylsulfonyl;Het³; Het³-alkyl; Het³-oxy; Het³-oxyalkyl; Het³-alkyloxy;Het³-oxyalkyloxy; Het³-carbonyl; Het³-thioalkyl; aryl; arylalkyl;aryloxy; aryloxyalkyl; arylalkyloxy; arylalkenyl; arylcarbonylalkyl;arylsulfonyl; —NR^(a)R^(b); alkyl-NR^(a)R^(b); O-alkyl-NR^(a)R^(b);—C(═O)—NR^(a)R^(b); —C(═O)-alkyl-NR^(a)R^(b); andO-alkyl-C(═O)—NR^(a)R^(b); wherein R^(a) and R^(b) are selected from thegroup of hydrogen, alkyl, alkylcarbonyl, arylalkyl, alkyloxyalkyl, Het³,Het³alkyl, alkylsulfonyl, alkyl-NR^(c)R^(d) and C(═O)alkyl-NR^(c)R^(d),wherein R^(c) and R^(d) are selected from the group of hydrogen, alkyland alkylcarbonyl; or two radicals R⁴ may be combined to form a bivalentradical —X¹—C₁₋₆—X²— wherein C₁₋₆ is a saturated or unsaturated,straight or branched hydrocarbon radical having 1 to 6 carbon atoms andX¹ and X² are each independently C or O.

In another embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein two radicals R⁴may be combined to form a bivalent radical selected from the group of—CH₂CH₂—O—; —O—CH₂—O—; and —O—CH₂CH₂—O—.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein Het¹ is selectedfrom the group of tetrahydropyranyl and pyridinyl; wherein each radicalHet¹ is optionally substituted with 1, 2 or 3 polyhaloC₁₋₃alkylsubstituents.

In one embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein Het³ is selectedfrom the group of pyridinyl; pyrimidinyl; pyridazilyl; pyrazinyl;piperidinyl; pyrrolidinyl; piperazinyl; triazolyl; tetrahydropyranyl;tetrahydro-thiopyran-1,1-dioxide; thiazolyl; oxazolyl; morpholinyl;oxadiazolyl; imidazolyl; benzoxazolyl; benzothienyl; benzofuranyl;1,2,3,4-tetrahydroisoquinolinyl; indolyl; indolinyl; phthalazyl; andbenzo[1,3]dioxyl. In one embodiment, each radical is optionallysubstituted with 1, 2 or 3 substituents, each independently from eachother, selected from the group of halo, C₁₋₆alkyl, polyhaloC₁₋₃alkyl,cyano, hydroxy, oxo, ethanoyl, phenyl, pyrrolidinyl, piperidinyl,pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C₁₋₃alkyloxy.

In one further embodiment, the invention relates to a compound accordingto general Formula (I), a pharmaceutically acceptable acid or baseaddition salt thereof, a stereochemically isomeric form thereof, anN-oxide form thereof or a quaternary ammonium salt thereof, wherein

-   V¹ is selected from the group of a covalent bond, —CH₂—; —CH₂—CH₂—;    —CH₂—CH₂—CH₂—; —CH₂—CH═CH—; —CH₂—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃)—CH₂—;    —CH(CH₃)—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃—)CH₂—CH₂—; and    —CH₂—CH₂—CH(CH₃)—CH₂—;-   M¹ is selected from the group of hydrogen; cycloC₃₋₇alkyl; phenyl;    biphenyl; phenyloxy; benzyloxy; furanyl; and pyridinyl; wherein M¹    is optionally substituted with one or more radicals selected from    the group of halo; C₁₋₃alkyl; polyhaloC₁₋₃alkyl;    polyhaloC₁₋₃alkyloxy; and C₁₋₃allyloxy;-   L is selected from the group of covalent bond; —O—; —OCH₂—;    —OCH₂CH₂—; —OCH₂CH₂O—; —OCH₂CH₂OCH₂—; —NR⁷—; —NR⁷CH₂—;    —NR⁷cycloC₃₋₇; —OCH₂CH₂N(R⁷)CH₂—; —CH₂CH₂—; —C≡C—; —C═O—; and    —CH═CH—; wherein each of R⁷, independently of each other, is    selected from the group of hydrogen and C₁₋₃alkyl;-   R² and R³ are each independently of each other hydrogen, halo or    alkyl;-   A is selected from the group of phenyl, piperazinyl, and    piperidinyl, wherein each radical is optionally substituted with n    radicals R⁴, wherein n is an integer equal to zero or 1;-   R⁴ is selected from the group of halo; cyano; hydroxy; ethanoyl;    alkyl; alkyloxy; alkyloxyalkyl; alkyloxycarbonyl;    alkyloxycarbonylalkyl; alkylcarbonyl; alkylcarbonyloxy;    alkylcarbonylalkyloxy; polyhaloC₁₋₃alkyl; polyhaloC₁₋₃-alkyloxy;    polyhaloC₁₋₃alkylthio; alkylthio; alkylsulfonyl; Het³; Het³-alkyl;    Het³-oxy; Het³-oxyalkyl; Het³-alkyloxy; Het³-oxyalkyloxy;    Het³-carbonyl; Het³-thioalkyl; aryl; arylalkyl; aryloxy;    aryloxyalkyl; arylalkyloxy; arylalkenyl; arylcarbonylalkyl;    arylsulfonyl; —NR^(a)R^(b); alkyl-NR^(a)R^(b); O-alkyl-NR^(a)R^(b);    —C(═O)—NR^(a)R^(b); —C(═O)-allyl-NR^(a)R^(b); and    O-alkyl-C(═O)—NR^(a)R^(b); wherein R^(a) and R^(b) are selected from    the group of hydrogen, alkyl, alkylcarbonyl, arylalkyl,    alkyloxyalkyl, Het³, Het³alkyl, alkylsulfonyl, alkyl-NR^(c)R^(d),    and C(═O)alkyl-NR^(c)R^(d), wherein R^(c) and R^(d) are selected    from the group of hydrogen, alkyl and alkylcarbonyl; or two radicals    R⁴ may be combined to form a bivalent radical selected from the    group of —CH₂CH₂—O—; —O—CH₂—O—; and —O—CH₂CH₂—O—;-   Het¹ is selected from the group of tetrahydropyranyl and pyridinyl;    wherein each radical Het¹ is optionally substituted with 1, 2 or 3    polyhaloC₁₋₃alkyl substituents;-   Het² is selected from the group of piperazinyl; piperidinyl;    thienyl; furanyl; 1H-indazolyl; 1H-benzimidazolyl;    1,2,3,4-tetrahydro-isoquinolinyl; 2,5-diaza-bicyclo[2.2.1]heptyl;    pyrrolidinyl; azetidinyl; 2,7-diaza-spiro[3.5]-nonyl; pyridinyl;    pyrazolyl; indolinyl; 1H-indolyl; 1H-indazolyl; benzomorpholinyl;    thiazolyl; 1,2,3,4-tetrahydroquinolinyl; 3,9-diazaspiro[5.5]undecyl;    1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolinyl;    1,2,3,4,4a,10a-hexahydrobenzo[5,6][1,4]dioxino[2,3-c]pyridinyl;    2,3,4,9-tetrahydro-1H-indeno[2,1-c]-pyridinyl;    2,3,4,9-tetrahydro-1H-carbolinyl;    1,2,3,4-tetrahydro-benzo[4,5]-furo[2,3-c]pyridinyl;    1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridinyl; [1,4]diazepyl;    isoxazolyl; indanyl; and indolyl;-   Het³ is selected from the group of pyridinyl; pyrimidinyl;    pyridazilyl; pyrazinyl; piperidinyl; pyrrolidinyl; piperazinyl;    triazolyl; tetrahydropyranyl; tetrahydro-thiopyran-1,1-dioxide;    thiazolyl; oxazolyl; morpholinyl; oxadiazolyl; imidazolyl;    benzoxazolyl; benzothienyl; benzofuranyl;    1,2,3,4-tetrahydroisoquinolinyl; indolyl; indolinyl; phthalazyl; and    benzo[1,3]dioxyl; wherein each radical is optionally substituted    with 1, 2 or 3 substituents, each independently from each other,    selected from the group of halo, C₁₋₆alkyl, polyhaloC₁₋₃alkyl,    cyano, hydroxy, oxo, ethanoyl, phenyl, pyrrolidinyl, piperidinyl,    pyridinyl, morpholinyl, mono- and di(alkyl)amino, and C₁₋₃alkyloxy;-   aryl is phenyl or biphenyl; wherein each radical is optionally    substituted with 1, 2 or 3 substituents, each independently from    each other selected from the group of halo, C₁₋₃alkyl,    polyhaloC₁₋₃alkyl, polyhaloC₁₋₃alkyloxy, cyano, nitro,    ethyloxycarbonyl, and C₁₋₃alkyloxy; and-   alkyl is a saturated, straight or branched hydrocarbon radical    having from 1 to 6 carbon atoms; or is a saturated, cyclic    hydrocarbon radical having from 3 to 7 carbon atoms; or is saturated    hydrocarbon radical from 4 to 12 carbonatoms, comprising at least    one saturated, straight or branched hydrocarbon radical having from    1 to 6 carbon atoms and at least one saturated, cyclic hydrocarbon    radical having from 3 to 7 carbon atoms; wherein each carbon atom    may optionally be substituted with one or more radicals selected    from the group of cyano, hydroxy, carboxyl, carbamoyl, phenyl, and a    bivalent radical —OCH₂CH₂O—.

In further embodiment, the invention relates to a compound according togeneral Formula (I), a pharmaceutically acceptable acid or base additionsalt thereof, a stereochemically isomeric form thereof, an N-oxide formthereof or a quaternary ammonium salt thereof, wherein the compound isselected from the group of:

-   4-(4-(N-acetylmethyl)phenyl)-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-179);-   4-(3,4-dimethoxyphenyl)-3-cyano-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-110);-   3-cyano-4-(3-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1)-one    (compound 1-114);-   3-cyano-4-(4-hydroxypropylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-095);-   3-cyano-4-(4-methoxymethylphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-103);-   3-cyano-4-(2-fluoro-4-methoxyphenyl)-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-113);-   3-cyano-4-(4-(N-morpholyl)phenyl)-1-(3-methylbutyl)pyridine-2(1H)-one    (compound 1-223);-   3-cyano-1-(3-methylbutyl)-4-(phenylethynyl)pyridine-2(1H)-one    (compound 1-267);-   3-cyano-1-butyl-4-[4-(2-methyl-pyridin-4-yloxy)-phenyl]-pyridine-2(1H)-one    (compound 1-064); and-   3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one    (compound 4-047).

In the framework of this application, alkyl is a saturated, straight orbranched hydrocarbon radical having from 1 to 6 carbon atoms; or is asaturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms;or is a saturated hydrocarbon radical from 4 to 12 carbonatoms,comprising at least one saturated, straight or branched hydrocarbonradical having from 1 to 6 carbon atoms and at least one saturated,cyclic hydrocarbon radical having from 3 to 7 carbon atoms; wherein eachcarbon atom may optionally be substituted with one or more radicalsselected from the group of halo, polyhaloC₁₋₃alkyl, cyano, hydroxy,amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl, carbamoyl, phenyl,and a bivalent radical —OCH₂CH₂O—. In one embodiment, alkyl is methyl,ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment, each carbonatom is optionally substituted with one or more radicals selected fromthe group of cyano, hydroxy, carboxyl, carbamoyl, phenyl, and thebivalent radical —OCH₂CH₂O—.

The notation C₁₋₆alkyl defines a saturated, straight or branchedhydrocarbon radical having from 1 to 6 carbon atoms, such as C₆alkyl;C₅alkyl; C₄alkyl; C₃alkyl; C₂alkyl; and C₁alkyl. Examples of C₁₋₆alkylare methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, pentyl, andheptyl.

The notation cycloC₃₋₇alkyl defines a saturated, cyclic hydrocarbonradical having from 3 to 7 carbon atoms, such as cycloC₇alkyl;cycloC₆alkyl; cycloC₆alkyl; cycloC₅alkyl; cycloC₄alkyl; cycloC₃alkyl;and cycloC₃alkyl. Examples of cycloC₃₋₇alkyl are cyclopropyl,cyclobutyl, cyclopentyl, cycloheptyl, and cyclohexyl.

The notation C₁₋₃alkyl defines a saturated, straight or branchedhydrocarbon radical having from 1 to 3 carbon atoms, such as methyl,ethyl, n-propyl and isopropyl.

In one preferred embodiment, alkyl is C₁₋₆alkyl; in another preferredembodiment alkyl is C₃₋₇cycloalkyl.

In the framework of this application, alkenyl is alkyl, additionallycontaining one or more double bonds.

In the framework of this application, aryl is naphthyl, phenyl orbiphenyl; wherein each radical is optionally substituted with 1, 2 or 3substituents, each independently from each other selected from the groupof halo, C₁₋₃alkyl, polyhaloC₁₋₃alkyl, polyhaloC₁₋₃alkyloxy, cyano,hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, ethanoyl,ethyloxycarbonyl, and C₁₋₃alkylox. More preferred, aryl is phenyl orbiphenyl. More preferred, aryl is optionally substituted with 1, 2 or 3substituents, each independently from each other, selected from thegroup of halo, C₁₋₃alkyl, polyhaloC₁₋₃alkyl, polyhaloC₁₋₃alkyloxy,cyano, nitro, ethyloxycarbonyl, and C₁₋₃alkyloxy. More preferred, arylis phenyl or biphenyl, optionally substituted with 1, 2 or 3substituents, each independently from each other, selected from thegroup of halo, C₁₋₃alkyl, polyhaloC₁₋₃alkyl, polyhaloC₁₋₃alkyloxy,cyano, nitro, ethyloxycarbonyl, and C₁₋₃alkyloxy.

In the framework of this application, halo is a substituent selectedfrom the group of fluoro, chloro, bromo and iodo. Preferably, halo isbromo, fluoro or chloro.

In the framework of this application, polyhaloC₁₋₃alkyl is a straight orbranched saturated hydrocarbon radical having from 1 to 3 carbon atoms,wherein one or more carbon atoms is substituted with one or morehalo-atoms. Preferably, polyhaloalkyl is trifluoromethyl.

In the framework of this application, with “compounds according to theinvention” is meant a compound according to the general Formula (I), apharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof, an N-oxide form thereof or aquaternary ammonium salt thereof.

The pharmaceutically acceptable acid addition salts are defined tocomprise the therapeutically active non-toxic acid addition salts formsthat the compounds according to Formula (I) are able to form. Said saltscan be obtained by treating the base form of the compounds according toFormula (I) with appropriate acids, for example inorganic acids, forexample hydrohalic acid, in particular hydrochloric acid, hydrobromicacid, sulphuric acid, nitric acid and phosphoric acid; organic acids,for example acetic acid, hydroxyacetic acid, propanoic acid, lacticacid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleicacid, fumaric acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylicacid and pamoic acid.

Conversely said acid addition salt forms can be converted into the freebase form by treatment with an appropriate base.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic metal oramine addition salts forms (base addition salts) by treatment withappropriate organic and inorganic bases. Appropriate base salts formscomprise, for example, the ammonium salts, the alkaline and earthalkaline metal salts, in particular lithium, sodium, potassium,magnesium and calcium salts, salts with organic bases, e.g. thebenzathine, N-methyl-D-glucamine, hybramine salts, and salts with aminoacids, for example arginine and lysine.

Conversely, said salts forms can be converted into the free forms bytreatment with an appropriate acid.

Quaternary ammonium salts of compounds according to Formula (I) definessaid compounds which are able to form by a reaction between a basicnitrogen of a compound according to Formula (I) and an appropriatequaternizing agent, such as, for example, an optionally substitutedalkylhalide, arylhalide or arylalkylhalide, in particular methyliodideand benzyliodide. Other reactants with good leaving groups may also beused, such as, for example, alkyl trifluoromethanesulfonates, alkylmethanesulfonates and alkyl p-toluenesulfonates. A quaternary ammoniumsalt has a positively charged nitrogen. Pharmaceutically acceptablecounterions include chloro, bromo, iodo, trifluoroacetate and acetateions.

The term addition salt as used in the framework of this application alsocomprises the solvates that the compounds according to Formula (I) aswell as the salts thereof, are able to form. Such solvates are, forexample, hydrates and alcoholates.

The N-oxide forms of the compounds according to Formula (I) are meant tocomprise those compounds of Formula (I) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein one or more tertiary nitrogens (e.g. of the piperazinyl orpiperidinyl radical) are N-oxidized. Such N-oxides can easily beobtained by a skilled person without any inventive skills and they areobvious alternatives for the compounds according to Formula (I) sincethese compounds are metabolites, which are formed by oxidation in thehuman body upon uptake. As is generally known, oxidation is normally thefirst step involved in drug metabolism (Textbook of Organic Medicinaland Pharmaceutical Chemistry, 1977, pages 70-75). As is also generallyknown, the metabolite form of a compound can also be administered to ahuman instead of the compound per se, with much the same effects.

The compounds of Formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of Formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of Formula (I) areobviously intended to be embraced within the scope of this invention.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

The invention also comprises derivative compounds (usually called“pro-drugs”) of the pharmacologically-active compounds according to theinvention, which are degraded in vivo to yield the compounds accordingto the invention. Pro-drugs are usually (but not always) of lowerpotency at the target receptor than the compounds to which they aredegraded. Pro-drugs are particularly useful when the desired compoundhas chemical or physical properties that make its administrationdifficult or inefficient. For example, the desired compound may be onlypoorly soluble, it may be poorly transported across the mucosalepithelium, or it may have an undesirably short plasma half-life.Further discussion on pro-drugs may be found in Stella, V. J. et al.,“Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985,29, pp. 455-473.

Pro-drugs forms of the pharmacologically-active compounds according tothe invention will generally be compounds according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,having an acid group which is esterified or amidated. Included in suchesterified acid groups are groups of the formula —COOR^(x), where R^(x)is a C₁₋₆alkyl, phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula —CONR^(Y)R^(z), whereinR^(y) is H, C₁₋₆alkyl, phenyl or benzyl and R^(z) is —OH, H, C₁₋₆alkyl,phenyl or benzyl. Compounds according to the invention having an aminogroup may be derivatised with a ketone or an aldehyde such as, forexample, formaldehyde to form a Mannich base. This base will hydrolyzewith first order kinetics in aqueous solution.

In the framework of this application, with “compounds according to theinvention” is meant a compound according to the general Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, the N-oxide form thereof and aprodrug thereof.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. In particular, when hydrogen ismentioned, it is understood to refer to ¹H, ²H, ³H and mixtures thereof;when carbon is mentioned, it is understood to refer to ¹¹C, ¹²C, ¹³C,¹⁴C and mixtures thereof; when nitrogen is mentioned, it is understoodto refer to ¹³N, ¹⁴N, ¹⁵N and mixtures thereof; when oxygen ismentioned, it is understood to refer to ¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O andmixtures thereof; and when fluor is mentioned, it is understood to referto ¹⁸F, ¹⁹F and mixtures thereof.

The compounds according to the invention therefore also comprisecompounds with one or more isotopes of one or more element, and mixturesthereof, including radioactive compounds, also called radiolabelledcompounds, wherein one or more non-radioactive atoms has been replacedby one of its radioactive isotopes. By the term “radiolabelled compound”is meant any compound according to Formula (I), an N-oxide form, apharmaceutically acceptable addition salt or a stereochemically isomericform thereof, which contains at least one radioactive atom. For example,compounds can be labelled with positron or with gamma emittingradioactive isotopes. For radioligand-binding techniques (membranereceptor assay), the ³H-atom or the ¹²⁵I-atom is the atom of choice tobe replaced. For imaging, the most commonly used positron emitting (PET)radioactive isotopes are ¹¹C, ¹⁸F, ¹⁵O and ¹³N, all of which areaccelerator produced and have half-lives of 20, 100, 2 and 10 minutesrespectively. Since the half-lives of these radioactive isotopes are soshort, it is only feasible to use them at institutions which have anaccelerator on site for their production, thus limiting their use. Themost widely used of these are ¹⁸F, ^(99m)Tc, ²⁰¹Tl and ¹²³I. Thehandling of these radioactive isotopes, their production, isolation andincorporation in a molecule are known to the skilled person.

In particular, the radioactive atom is selected from the group ofhydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, theradioactive atom is selected from the group of hydrogen, carbon andhalogen.

In particular, the radioactive isotope is selected from the group of ³H,¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably,the radioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

A. Preparation of the Final Compounds Experimental Procedure 1 L is aCovalent Bond

The final compounds according to Formula (I-a), wherein L is a covalentbond, can be prepared by reacting an intermediate compound of Formula(II) with a compound of Formula (III) according to reaction scheme (1),a reaction that is performed in a suitable reaction-inert solvent, suchas, for example, 1,4-dioxane or mixtures of inert solvents such as, forexample, 1,4-dioxane/DMF, in the presence of a suitable base, such as,for example, aqueous NaHCO₃ or Na₂CO₃, a Pd-complex catalyst such as,for example, Pd(PPh₃)₄ under thermal conditions such as, for example,heating the reaction mixture at 150° C. under microwave irradiation, forexample for 10 min. In a reaction suitable for Pd mediated coupling withboronic acids or boronic esters, such as, for example, a halo, triflateor pyridinium moiety. Such intermediate compounds may be preparedaccording to reaction schemes (8), (9) and (10) (see below). R⁵ and R⁶may be hydrogen or alkyl, or may be taken together to form for examplethe bivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or—C(CH₃)₂C(CH₃)₂—.

Experimental Procedure 2 L is Oxygen or Sulfur

The final compounds according to Formula (I-b), wherein L is oxygen orsulfur, can be prepared by reacting an intermediate compound of Formula(II) with a compound of Formula (IV) according to reaction scheme (2), areaction that is performed in a suitable reaction-inert solvent, suchas, for example, THF, in the presence of a suitable base, such as, forexample, NaH, under thermal conditions such as, for example, heating thereaction mixture for example at 80° C. under microwave irradiation for10 minutes. In reaction scheme (2), all variables are defined as inFormula (I), R¹ is V¹-M¹ and Y is a suitable leaving group, such as, forexample, pyridinium.

Experimental Procedure 3 L is Aminoalkyl

The final compounds according to Formula (I-c), wherein L is —NR⁷—;—NR⁷CH₂—; or —NR⁷CH₂CH₂— wherein each of R⁷, independently of eachother, is selected from the group of hydrogen and alkyl, can be preparedby reacting an intermediate compound of Formula (II) with a compound ofFormula (V) according to reaction scheme (3), a reaction that isperformed in a suitable reaction-inert solvent, such as, for example,1,4-dioxane, in the presence of a suitable base, such as, for example,K₃PO₄, a Pd-complex catalyst such as, for example,

under thermal conditions such as, for example, heating the reactionmixture for example at 80° C. for 12 hours. In reaction scheme (3), allvariables are defined as in Formula (I), R¹ is V¹-M¹ and Y is a suitablegroup for Pd-mediated coupling with amines, such as, for example, halo.Alternatively, compounds according to Formula (I-c) can be prepared byreacting an intermediate compound of Formula (II) with a compound ofFormula (V) according to reaction scheme (3), a reaction that isperformed in a suitable reaction-inert solvent, such as, for example,dimethoxyethane or acetonitrile, in the presence of a suitable base,such as, for example, Cs₂CO₃ or N,N-diisopropylethylamine, under thermalconditions such as, for example, heating the reaction mixture forexample at 160° C. under microwave irradiation for 30 minutes.

Experimental Procedure 4 L is Alkynyl

The final compounds according to Formula (I-d), wherein L is —C≡C—, canbe prepared by reacting an intermediate compound of Formula (II) with acompound of Formula (VI) according to reaction scheme (4), a reactionthat is performed in a suitable reaction-inert solvent, such as, forexample, THF, in the presence of a suitable base, such as, for example,NEt₃, a Pd-complex catalyst such as, for example, PdCl₂(PPh₃)₂ aphosphine such as, for example, PPh₃, a copper salt such as, forexample, CuI and under thermal conditions such as, for example, heatingthe reaction mixture for example at 80° C. for 12 hours. In reactionscheme (4), all variables are defined as in Formula (I), R¹ is V¹-M¹ andY is a group suitable for Pd-mediated coupling with alkynes, such as,for example, halo.

Experimental Procedure 5 L is Alkenyl

The final compounds according to Formula (I-e), wherein L is—C(R⁸)═C(R⁹)— can be prepared by reaction of an intermediate of Formula(II) with an intermediate of Formula (VII) in an inert solvent such as,for example, 1,4-dioxane, in the presence of a suitable base, such as,for example, NaHCO₃ or Na₂CO₃, a Pd-complex catalyst such as, forexample, Pd(PPh₃)₄ under thermal conditions such as, for example,heating the reaction mixture at 85° C., for example for 8 hours. Inreaction scheme (5), all variables are defined as in Formula (I) and Yis a group suitable for Pd-mediated coupling with boronic acids orboronic esters, such as, for example, a halo, trifluoromethanesulphonylor pyridinium moiety. Such intermediate compounds may be preparedaccording to reaction schemes (8), (9) and (10) (see below). R⁵ and R⁶may be hydrogen or alkyl, or may be taken together to form for examplethe bivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or—C(CH₃)₂C(CH₃)₂—. In reaction scheme (5), all variables are defined asin Formula (I) and R¹ is V¹-M¹.

Experimental Procedure 6

The final compounds according to Formula (I-e2), wherein L is —CH═CH—and Formula (I-f2), wherein L is —CH₂CH₂—, can be prepared by art-knownprocedures such as, for example, hydrogenation of a final compound ofFormula (I-d), prepared according to reaction scheme (6). Additionally,final compounds of Formula (I-f1) and Formula (I-f2) can be preparedfrom final compounds of Formula (I-c1) and Formula (I-c2) by art-knownhydrogenation methods according to reaction scheme (6). Additionally,final compounds of Formula (I-e2) can be prepared by partial reductionof the triple bond of final compounds of Formula (I-d) by art knownprocedures. In reaction scheme (6), all variables are defined as inFormula (I) and R¹ is V¹-M¹.

Experimental Procedure 7

The compounds according to Formula (I) can be prepared by art knownprocedures by reacting a compound of Formula (VIII) with an alkylatingagent of Formula (IX), such as, for example, isopentylbromide, using asuitable base such as, for example, K₂CO₃, and an iodine salt such as,for example, KI, in an inert solvent such as, for example, acetonitrileat a moderately high temperature such as, for example, 120° C. Inreaction scheme (7), all variables are defined as in Formula (I), R¹ isV¹-M¹ and Z is a suitable leaving group such as, for example, halo.

Additionally, final compounds according to Formula (I) can be preparedby a skilled person using art known procedures by further modificationsof final compounds of Formula (I-a), (I-b), (I-c), (I-d), (I-c) and(I-f) such as, for example:

-   -   Alkylation of final compounds of Formula (I-a), (I-b), (I-c),        (I-d), (I-e) and (I-f) that contain in their structure one or        more hydroxy- or amino-substituents with a suitable alkylating        agent under thermal conditions using a suitable base.    -   Saponification of final compounds of Formula (I-a), (I-b),        (I-c), (I-d), (I-e) and (I-f) that contain in their structure        one or more alkyloxycarbonyl function by using a suitable        saponificating agent such as, for example, NaOH or LiOH.    -   Reaction of final compounds of Formula (I-a), (I-b), (I-c),        (I-d), (I-e) and (I-f) that contain in their structure one or        more carboxylic acid function with ammonia or a primary or        secondary amine by using a suitable coupling agent such as, for        example O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate, to yield the corresponding final compounds        of Formula (I), bearing a primary, secondary or tertiary        carboxamide function in their structures.    -   Reaction of final compounds of Formula (I-a), (I-b), (I-c),        (I-d), (I-e) and (I-f) that contain in their structure a primary        or secondary amine function with a carboxylic acid by using a        suitable coupling agent such as, for example,        O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate to yield the corresponding final compounds        of Formula (I), bearing a primary, secondary or tertiary        carboxamide function in their structures.    -   Reductive amination of final compounds of Formula (I-a), (I-b),        (I-c), (I-d), (I-e) and (I-f) that contain in their structure        one or more amino-substituents with a suitable aldehyde under        thermal conditions using a suitable reducing agent such as, for        example, sodium cyanoborohydride.    -   Reaction of final compounds of Formula (I-a), (I-b), (I-c),        (I-d), (I-e) and (I-f) that contain in their structure one or        more hydroxy-substituents with an alcohol derivative by using a        suitable coupling system such as, for example,        di-tert-butylazodicarboxylate/triphenylphosphine under thermal        conditions.    -   1,3-Dipolar cycloaddition of final compounds of Formula (I-a),        (I-b), (I-c), (I-d), (I-e) and (I-f) that contain in their        structure a reactive double or triple bond with a suitable        dipole to yield the corresponding [3+2] adduct final compounds.

B. Preparation of the Intermediate Compounds Experimental Procedure 8

Intermediate compounds of Formula (II-a) can be prepared by reacting anintermediate of Formula (X) with a suitable halogenating agent such as,for example, P(═O)Br₃, a reaction that is performed in a suitablereaction-inert solvent such as, for example, DMF, at a moderatelyelevated temperature such as, for example, 110° C. In reaction scheme(8), all variables are defined as in Formula (I) and R¹ is V¹-M¹.

Experimental Procedure 9

Intermediate compounds of Formula (II-b) can be prepared by reacting anintermediate of Formula (X) with triflic anhydride (also calledtrifloromethanesulfonic anhydride), a reaction that is performed in asuitable reaction-inert solvent such as, for example, dichloromethane,in the presence of a base such as, for example, pyridine at a lowtemperature such as, for example, −78° C. In reaction scheme (9), allvariables are defined as in Formula (I) and R¹ is V¹-M¹.

Experimental Procedure 10

Intermediate compounds of Formula (II-c) can be prepared by reacting anintermediate compound of Formula (II-b) with pyridine, at a moderatelylow temperature such as, for example, 40° C. In reaction scheme (10),all variables are defined as in Formula (I) and R¹ is V¹-M¹.

Experimental Procedure 11

Intermediate compounds of Formula (X) can be prepared by art knownprocedures by reacting an intermediate compound of Formula (XI) with asuitable reagent for methylether-cleavage, such as, for example, NaOH,in a solvent such as, for example, water at a moderately hightemperature such as, for example, 100° C. In reaction scheme (11), allvariables are defined as in Formula (I) and R¹ is V¹-M¹.

Experimental Procedure 12

Intermediate compounds of Formula (XI) can be prepared by art knownprocedures by reacting an intermediate of Formula (XII) with analkylating agent of Formula (IX), such as, for example,isopentylbromide, using a base such as, for example, K₂CO₃, and,optionally an iodine salt such as, for example, KI, in an inert solventsuch as, for example, acetonitrile at a moderately high temperature suchas, for example, 120° C. In reaction scheme (12), all variables aredefined as in Formula (I), R¹ is V¹-M¹ and Z is a suitable leaving groupsuch as, for example, halo.

Experimental Procedure 13

Intermediate compounds of Formula (III) can be prepared by art knownprocedures by reacting an intermediate of Formula (XIII) with a suitableboron source such as, for example, bis(pinacolato)diboron in thepresence of a Palladium catalyst such as, for example,1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride in a inertsolvent such as, for example, dichloromethane, in the presence of asuitable salt such as, for example, potassium acetate at moderately hightemperature such as, for example, 110° C. for as for example 16 hours.Additionally, compounds of Formula (III) can be prepared by art knownprocedures of metal-halogen exchange and subsequent reaction with anappropriate boron source from compounds of Formula (XIII). Thus forexample reaction of an intermediate compound of Formula (XIII) with anorganolithium compound such as, for example, n-butyllithium at amoderately low temperature such as, for example, −40° C. in an inertsolvent such as, for example, THF followed by subsequent reaction withan appropriate boron source such as, for example, trimethoxyborane. Inreaction scheme (13), all variables are defined as in Formula (I) and R⁵and R⁶ may be hydrogen or alkyl, or may be taken together to form forexample the bivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or—C(CH₃)₂C(CH₃)₂—.

The starting materials of Formula (X) and the intermediate compoundsaccording to Formula (III), (IV), (V), (VI), (VII), (IX), (XII) and(XIII) are compounds that are either commercially available or may beprepared according to conventional reaction procedures generally knownin the art.It is evident that in the foregoing and in the following reactions, thereaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art, such as, for example, extraction, crystallization andchromatography. It is further evident that reaction products that existin more than one enantiomeric form, may be isolated from their mixtureby known techniques, in particular preparative chromatography, such as,for example, preparative HPLC.Pharmacology

The compounds provided in this invention are positive allostericmodulators of metabotropic receptors, in particular they are positiveallosteric modulators of mGluR2. The compounds of the present inventiondo not appear to bind to the glutamate recognition site, the orthostericligand site, but instead to an allosteric site within the seventransmembrane region of the receptor. In the presence of glutamate or anagonist of mGluR2, the compounds of this invention increase the mGluR2response. The compounds provided in this invention are expected to havetheir effect at mGluR2 by virtue of their ability to increase theresponse of such receptors to glutamate or mGluR2 agonists, enhancingthe response of the receptor. Hence, the present invention relates to acompound for use as a medicine, as well as to the use of a compoundaccording to the invention or a pharmaceutical composition according tothe invention for the manufacture of a medicament for treating orpreventing a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of mGluR2 allosteric modulators, in particular positive mGluR2allosteric modulators.

Also, the present invention relates to the use of a compound accordingto the invention or a pharmaceutical composition according to theinvention for the manufacture of a medicament for treating, orpreventing, ameliorating, controlling or reducing the risk of variousneurological and psychiatric disorders associated with glutamatedysfunction in a mammal, including a human, the treatment or preventionof which is affected or facilitated by the neuromodulatory effect ofmGluR2 positive allosteric modulators.

Where the invention is said to relate to the use of a compound orcomposition according to the invention for the manufacture of amedicament for e.g. the treatment of a mammal, it is understood thatsuch use is to be interpreted in certain jurisdictions as a method ofe.g. treatment of a mammal, comprising administering to a mammal in needof such e.g. a treatment, an effective amount of a compound orcomposition according to the invention.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancetolerance, substance withdrawal (including substances such as, forexample, opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic states, severe pain, intractable pain, neuropathicpain, and post-traumatic pain), tardive dyskinesia, sleep disorders(including narcolepsy), attention deficit/hyperactivity disorder, andconduct disorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder Preferably, the central nervoussystem disorder is a personality disorder selected from the group ofobsessive-compulsive personality disorder and schizoid, schizotypaldisorder.

Preferably, the central nervous system disorder is a substance-relateddisorder selected from the group of alcohol abuse, alcohol dependence,alcohol withdrawal, alcohol withdrawal delirium, alcohol-inducedpsychotic disorder, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, nicotine dependence, nicotinewithdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof, an N-oxide form thereof or aquaternary ammonium salt thereof.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salt thereof, a stereochemically isomeric form thereof, anN-oxide form thereof or a quaternary ammonium salt thereof, or anysubgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, in particular, for administration orally,rectally, percutaneously, by parenteral injection or by inhalation. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as, for example, suspensions, syrups, elixirs,emulsions and solutions; or solid carriers such as, for example,starches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules and tablets.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit forms in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, for example, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a trans-dermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, ininjectable solutions or suspensionsand the like, and segregated multiples thereof. Since the compoundsaccording to the invention are potent orally administrable dopamineantagonists, pharmaceutical compositions comprising said compounds foradministration orally are especially advantageous.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs in the treatment, prevention, control, amelioration,or reduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility as well as to the use ofsuch a composition for the manufacture of a medicament.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Experimental Part

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification. Specifically, the following abbreviationsmay be used in the examples and throughout the specification:

AcOEt (ethyl acetate) M (molar) AcOH (acetic acid) MeOH (methanol) BBr₃(boron tribromide) mg (milligrams) BINAP (±)-1,1′-Bi(2-naphthol) MgSO₄(magnesium sulphate) Br₂ (bromine) MHz (megahertz) CDCl₃ (deuteratedchloroform) min (minutes) CCl₄ (carbon tetrachloride) μl (microliters)DCM (dichloromethane) ml (milliliters) MCPBA (3-chloroperbenzoic acid)mmol (millimol) DEAD (diethyl azodicarboxylate) m.p. (melting point)DIBAL (diisobutyl aluminium hydride) NaBH(OAc)₃ (Sodium triacetoxyboro-hydride) DME (dimethoxyethane) Na₂CO₃ (sodium carbonate) DMF(dimethylformamide) NaH (sodium hydride) DMSO (dimethyl sulfoxide)NaHCO₃ (sodium bicarbonate) Dppf (1,1′-bis(diphenylphosphanyl)ferrocene)NaHMDS (sodium hexamethyldisilazane) EDCI•HCl(1-3(dimethylaminopropyl)-3- NaI (sodium iodide) ethylcarbodiimide,hydrochloride) Et₃N (triethylamine) NaO^(t)Bu (sodium tert-butoxide)Et₂O (diethyl ether) Na₂SO₄ (sodium sulphate) EtOH (ethanol) NBS(N-bromosuccinimide) g (grams) NH₄Cl (ammonium chloride) ¹H (proton)NH₄OH (ammonium hydroxide) H₂ (hydrogen) NMR (Nuclear MagneticReasonance) HCl (hydrochloric acid) Pd2(dba)₃ (palladium(II)dibenzylideneacetone) HPLC (High Pressure Liquid Chromatography)PdCl₂(dppf)₂ (Bis(1,1′-bis(diphenyl- phosphanyl)ferrocene palladium (II)di- chloride) Hz (Hertz) PdCl₂(PPh₃)₂ (Bis(triphenylphosphine) palladium(II) dichloride KBr (potassium bromide) Pd(OAc)2 (Palladium acetate)K₂CO₃ (potassium carbonate) Pd(PPh₃)₄(tetrakis(triphenylphosphine)palladium(0)) KOAc (potassium acetate)P(═O)Br₃ (phosphorousoxybromide) KI (potassium iodide) PPh₃(triphenylphosphine) KOtBu (potassium tert-butoxide) TFA(trifluoroacetic acid) KOH (potassium hydroxide) THF (tetrahydrofuran)K₃PO₄ (potassium phosphate) TLC (thin layer chromatography) LCMS (LiquidChromatography Mass Spectrum) Tf₂O (trifloromethanesulfonic anhydride)LiAlH₄ (lithium aluminium hydride) Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Celsius). All reactions are conducted not under an inertatmosphere at room temperature, unless otherwise noted.

Microwave assisted reactions were performed in a single-mode reactor:Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currentlyBiotage). Description of the instrument can be found inwww.personalchemistry.com. And in a multimode reactor: MicroSYNTHLabstation (Milestone, Inc.). Description of the instrument can be foundin www.milestonesci.com.

A. Preparation of the Intermediate Compounds

A1. Intermediate Compound 1

The reaction was carried out under N₂ atmosphere. To a solution ofcommercially available4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (1.00 g, 6.60 mmol,1 eq) in acetonitrile (45 ml) was added K₂CO₃ (2.73 g, 19.8 mmol, 3 eq)and isopentylbromide (441 mg, 8.65 mmol, 1.3 eq). The resulting solutionwas heated at 100° C. for 12 hours. The reaction was then cooled to roomtemperature and filtered through a pad of celite. The filtrate was thenconcentrated in vacuo. Subsequently, the crude residue thus obtained waspurified by flash chromatography (SiO₂, eluting with a gradient elutionof between 0-2% MeOH in DCM) to yield intermediate compound 1 as acreamy solid (82%, 5.40 mmol).

A2. Intermediate Compounds 2 and 2′

A solution of intermediate compound 1 (1.5 g, 6.81 mmol) in aqueous NaOH(0.1 N, 75 ml) and THF (20 ml) was heated to 100° C. for 1 hour. Thereaction was cooled to 0° C. and acidified by the addition of 1M HCl,adjusting the pH to about 3, at which point a white solid precipitated.The solid was filtered off and dried in vacuo to yield the N-isopentylsubstituted intermediate compound 2 as a white solid (1.3 g, 6.30 mmol).In an equal manner was prepared the N-n-butyl substituted intermediatecompound 2′.

A3. Intermediate Compounds 3, 3′ and 3″

The reaction was carried out under N₂ atmosphere. To a solution ofintermediate compound 2 (2.00 g, 9.66 mmol, 1 eq) in DMF (10 ml) wasadded cautiously P(═O)Br₃ (5.54 g, 19.0 mmol, 2 eq), the resultingsolution was then heated at 100° C. into a sealed tube for 2 hours. Thereaction was then cooled to room temperature and diluted by H₂O (30 ml),the resulting solution was subsequently extracted with AcOEt (3×30 ml).The organic layer was dried over Na₂SO₄ and concentrated in vacuo toyield an oil. The crude product was purified by flash chromatography(SiO₂, eluting with DCM) to yield N-isopentyl substituted intermediatecompound 3 as a creamy solid (2.13 g, 82%, 7.92 mmol). In an equalmanner was prepared the N-n-butyl substituted intermediate compound 3′and the N-methylcyclopropyl substituted intermediate compound 3″.

A4. Intermediate Compound 4

In a round flask containing intermediate compound 2 (100 mg, 0.48 mmol)in DCM (5 ml), were added 3 eq of pyridine (0.118 ml, 1.44 mmol). Themixture was cooled to −78° C. and Tf₂O (0.217 ml, 0.528 mmol) was addedslowly. The solution was warmed to room temperature and stirred for ½hour. The mixture was hydrolized with cold water, extracted with DCM(3×10 ml), washed twice with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure to yield intermediate compound 4 (133mg).

A6. Intermediate Compound 6

The reaction was carried out under nitrogen atmosphere. To a solution ofN-(2-bromobenzyl)-acetamide (468 mg, 2.02 mmol) in acetonitrile (45 ml)was added di-tert-butyl dicarbonate (1.34 g, 6.15 mmol) andN,N-dimethaminopyridine (501 mg, 4.1 mmol). The reaction mixture wasthen stirred at room temperature for 20 min, after which time it wasdiluted with AcOEt (40 ml) and washed with a saturated solution ofNaHCO₃ (2×40 ml) and a saturated solution of NH₄Cl (3×40 ml). Theorganic layer was then dried over Na₂SO₄ and concentrated in vacuo toyield a crude solid. This was purified by short open columnchromatography (SiO₂, eluting with 2% MeOH in DCM) to yield intermediatecompound 6 as a yellow oil (590.00 mg, 89%, 1.79 mmol).

A7. Intermediate Compound 7

To a solution of intermediate compound 6 (200 mg, 0.61 mmol) in DMSO (4ml) was added bis(pinacolato)diboron (232 mg, 0.913 mmol) and potassiumKOAc (180 mg, 1.83 mmol) the solution was then degassed using a streamof nitrogen and then to the reaction mixture was added1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (20.0mg, 0.0183 mmol). The reaction mixture was then heated at 110° C. undera nitrogen atmosphere for 16 hours. The reaction was then cooled to roomtemperature and diluted with AcOEt (30 ml) and the resulting solutionwas washed with water (3×15 ml), the organic fraction was then driedover Na₂SO₄ and concentrated in vacuo to yield the desired compound. Theproduct was purified by short open column chromatography (SiO₂, elutingwith DCM) to yield intermediate compound 7 as yellow oil (149.0 mg, 89%,0.054 mmol).

A8. Intermediate Compound 8

The reaction was carried out under N₂ atmosphere. 4-Bromobenzeneboronicacid pinacol cyclic ester (300 mg, 1.06 mmol), N-acetylethylenediamine(0.155 ml, 1.59 mmol), Xantphos (123 mg, 0.21 mmol), and Cs₂CO₃ (518 mg,1.59 mmol) were added to a mixture of 1,4-dioxane (5.88 ml) and DMF(0.12 ml) at room temperature, and N₂ was fluxed through the mixture for5 min. Pd(OAc)₂ (24 mg, 0.1 mmol) was added and the mixture wasirradiated under microwave conditions at 170° C. for 10 min into asealed tube. The reaction was then cooled to room temperature andfiltered through a pad of celited. The volatiles were evaporated invacuum and the residues thus obtained was purified by short open columnchromatography (SiO₂, eluting with DCM/MeOH(NH₃) to yield intermediatecompound 8 (80 mg).

A9. Intermediate Compound 9

To a solution of 4-pyridinethiol (149 mg, 1.35 mmol) in dimethylormamide(5 ml) was added K₂CO₃ (186 mg, 1.35 mmol); the resulting solution wasstirred for 12 min and to this subsequently was added a solution of2-(4-bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (400mg, 1.35 mmol) and the resulting solution was stirred for 2 hours. Themixture was then diluted by the addition of water (30 ml) and extractedwith AcOEt (3×15 ml); the organic layer was subsequently dried overNa₂SO₄ and concentrated in vacuo to yield the crude product. The crudereaction mixture was subsequently purified by Biotage purification(eluting with DCM) to yield intermediate compound 9. (406.0 mg, 1.24mmol, 92%).

A10. Intermediate Compound 10

Commercially available4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (4.70 g, 31.29 mmol,1 eq), 4-(trifluoromethoxy)benzylbromide (5.44 ml, 32.86 mmol, 1.05 eq)and K₂CO₃ (12.9 g, 93.8 mmol, 3 eq) were mixed in acetonitrile (200 ml).The mixture was heated at 140° C. for 16 hours into a sealed tube. Thereaction was then cooled to room temperature and the solvents wereevaporated in vacuum. The resulting residue was dissolved in DCM andfiltered through a pad of celite. The filtrate was then concentrated invacuo. Subsequently, the white solid thus obtained was triturated withdiethylether to yield intermediate compound 10 as a white solid (9.20 g,91%).

A11. Intermediate Compound 11

To a solution of intermediate compound 10 (9.20 g, 28.37 mmol) in THF(100 ml) was added aqueous NaOH (0.1 N, 300 ml). The reaction mixturewas heated at 100° C. for 4 hours. The reaction was then cooled to roomtemperature and the THF was evaporated in vacuum. The resulting basicaqueous phase was acidified by the addition of 2 N HCl, adjusting the pHto about 3, at which point a white solid precipitated. The solid wasfiltered off, washed with diethylether and dried in vacuo to yield theintermediate compound 11 as a white solid (8.05 g, 91%).

A12. Intermediate Compound 12

Intermediate compound 11 (6.57 g, 21.19 mmol, 1 eq) and P(═O)Br₃ (12.15g, 42.39 mmol, 2 eq) were mixed in DMF (125 ml) and the resultingmixture was then heated at 110° C. for 1 hour. The reaction was thencooled to room temperature and diluted with H₂O (200 ml), the resultingsolution was subsequently extracted with AcOEt (3×75 ml). The organiclayer was dried over MgSO₄ and concentrated in vacuo. The crude productwas purified by flash chromatography (SiO₂, eluting with DCM) to yieldintermediate compound 12 as a white solid (6.75 g). In a similar mannerwas made intermediate compound 12′ wherein the phenyl moiety in thepara-position is substituted with a fluor instead of a trifluoromethoxymoiety.

A13. Intermediate Compound 13

To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(500 mg, 2.27 mmol), N-(2-hydroxyethyl)morpholine (330.8 mg, 2.72 mmol)and PPh₃ polymer bound (loading 2.15 mmol/g) (2.11 g, 4.54 mmol) in dryDCM (30 ml) at 0° C. was added di-tert-butylazodicarboxylate (784.0 mg,3.40 mmol). The reaction mixture was stirred at room temperature for 2hours. Then, the resin was filtered off, washed with DCM and thefiltrate concentrated in vacuo. The residue (756.45 mg) was used in thenext reaction step without further purification

A14. Intermediate Compound 14

Intermediate compound 3 (200 mg, 0.74 mmol),1-tert-butoxycarbonylpiperazine (151 mg, 0.81 mmol), K₃PO₄ (236 mg, 1.1mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane(3 ml) at room temperature. The corresponding mixture was heated at 85°C. in a sealed tube for 16 hours. The mixture was cooled to roomtemperature, filtered through a pad of celite and washed with DCM. Thefiltrate was concentrated in vacuo and the residue thus obtained waspurified by flash chromatography to yield intermediate compound 14 (200mg, 72%).

A16. Intermediate Compound 16

A mixture of 5-(4-bromophenyl)-1,3-oxazole (220 mg, 0.98 mmol),bis(pinacolato)-diboron (372 mg, 1.47 mmol),1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, DCM (24 mg,0.0294 mmol), KOAc (288 mg, 2.93 mmol) in DMSO (7 ml) was heated at 110°C. for 16 hours. The mixture was cooled to room temperature, dilutedwith AcOEt (30 ml) and washed with water (3×15 ml). The combined organiclayers were dried over Na₂SO₄, evaporated in vacuum and the residue thusobtained (200 mg) was used in the next reaction step without furtherpurification.

A17. Intermediate Compound 17

A solution of commercially available4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (4.0 g, 0.0266 mol),beta-bromophenetole (5.62 g, 0.0279 mol) and K₂CO₃ (11.0 g, 0.0799 mol)in CH₃CN (150 ml) was heated at reflux for 16 hours. The reactionmixture was then filtered off and the filtrate concentrated in vacuo.The residue was recrystallised from ethylether to yield intermediatecompound 17 (7 g, 97%).

A18. Intermediate Compound 18

To a solution of intermediate compound 17 (7.0 g, 0.0259 mol) in MeOH(100 ml) was added aqueous NaOH (0.1 N, 200 ml). The reaction mixturewas heated to 100° C. for 3 hours. The reaction was then cooled to roomtemperature and the MeOH was evaporated in vacuum. The resulting basicaqueous phase was acidified by the addition of 2 N HCl, adjusting the pHto about 3, at which point a white solid precipitated. The solid wascollected using a sintered funnel, washed with ethylether and dried invacuo to yield intermediate compound 18 as white solid (5.78 g, 87%).

A19. Intermediate Compound 19

Intermediate compound 18 (7.10 g, 0.027 mol) and P(═O)Br₃ (15.886 g,0.055 mol) were mixed in DMF (150 ml) and the resulting mixture was thenheated at 110° C. for 3 hours. The reaction was then cooled to roomtemperature and diluted by H₂O (100 ml), the resulting solution wassubsequently extracted with AcOEt (3×150 ml). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash chromatography (SiO₂, eluting with DCM) to yieldintermediate compound 19 (7.67 g, 89%).

A20. Intermediate Compound 20

In a round flask containing 3-(trifluoromethyl)benzaldehyde ([454-89-7]CAS) (0.872 ml, 0.0065 mol) and 4-piperidinemethanol (0.5 g, 0.0043 mol)in DCE (20-30 ml) and a few drops of AcOH, NaBH(OAc)₃ (2.2 g, 0.0107mol) was added. The mixture was stirred overnight at room temperature,after which time it was washed with a saturated solution of NaHCO₃ andextracted with DCM. The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude product was purified by flashchromatography to yield intermediate compound 20 (0.610 g, 56%).

A23. Intermediate Compound 23

In a round flask containing methyl-4-formylbenzoate (5.6 g, 0.034 mol)and morpholine (2 g, 0.023 mol) in DCE (20 ml), few drops of AcOH andmolecular sieves (4A) were added. The reaction mixture was stirred atroom temperature for 40 min and NaBH(OAc)₃ (5 g, 0.023 mol) was added.The mixture was stirred overnight at room temperature, after which timeanother equivalent of NaBH(OAc)₃ (5 g, 0.023 mol) was added. The mixturewas stirred at room temperature for 5 hours and was subsequently washedwith HCl (1 N) and extracted with DCM. The organic layer was finallywashed with a saturated solution of NaHCO₃. The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash chromatography (DCM/MeOH(NH₃) mixtures) to yieldintermediate compound 23 (3 g, 60%)

A24. Intermediate Compound 24

The reaction was carried out under N₂ atmosphere. To a solution ofintermediate compound 23 (2 g, 0.0085 mol) in THF (12 ml), lithiumaluminum hydride (1 M in THF) (17 ml, 0.017 mol) was slowly added. Thereaction mixture was stirred at room temperature for 2 hours. Then, asaturated solution of NaHCO₃ was carefully added and the mixture wasextracted with DCM. The combined organic layers were dried over Na₂SO₄and concentrated in vacuo to yield intermediate compound 24 (1.75 g,100%) which was used in the next reaction step without furtherpurification.

A28. Intermediate Compound 28

A mixture of intermediate compound 3 (250 mg, 0.93 mmol),tributyl(vinyl)tin (0.325 ml, 1.11 mmol) and Pd(PPh₃)₄ (22 mg, 0.0186mmol) in degassed toluene (10 ml) was microwaved at 130° C. for 25 min.The mixture was then cooled to room temperature and solvents wereevaporated in vacuum. The residue was purified by flash chromatography(SiO₂, DCM/MeOH(NH₃) mixtures) to yield intermediate compound 28 (100mg, 50%) as pale yellow solid.

A29. Intermediate Compound 29

To a solution of 4-pyridylcarbinol (15 g, 137.4 mmol) in DCM (200 ml)was added thionyl chloride (43.6 ml) and the resulting reaction mixturewas stirred at room temperature for 4 h. The mixture was cooled to roomtemperature and the solvent was evaporated in vacuo. The residue wasdiluted with DCM and washed with a saturated solution of NaHCO₃. Thecombined organic layers were dried over Na₂SO₄ and concentrated in vacuoto yield intermediate compound 29 (17.18 g, 99%).

A30. Intermediate Compound 30

To a mixture of NaH (60% in mineral oil) (0.718 g, 17.96 mmol) in THF(20 ml), a solution of 5-bromoindole (2.34 g, 11.8 mmol) in THF (17 ml)was added dropwise. The resulting mixture was stirred at roomtemperature for 1 h. Then, intermediate compound 29 (1.81 g, 14.2 mmol)was added and the mixture was heated at 80° C. overnight. The cooledreaction mixture was washed with H₂O and extracted with AcOEt. Thecombined organic layers were dried over Na₂SO₄ and evaporated in vacuo.The residue was purified by flash chromatography (SiO₂, DCM/MeOHmixtures) to yield intermediate compound 30 (2.73 g, 80%).

A31. Intermediate Compound 31

To a solution of intermediate compound 30 (2.73 g, 9.5 mmol) in DMSO (27ml) was added bis(pinacolato)diboron (2.414 g, 9.5 mmol) and KOAc (2.8g, 28.5 mmol). The solution was then degassed using a stream of nitrogenand then to the reaction mixture was added1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.23g, 0.28 mmol). The reaction mixture was then heated at 110° C. overnightunder a nitrogen atmosphere. The reaction was then cooled to roomtemperature and additional amounts of bis(pinacolato)diboron (1.63 g,6.4 mmol), KOAc (1.89 g, 19.2 mmol) and1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM(0.155 g, 0.19 mmol) were added and the mixture was heated at 130° C.overnight. The cooled reaction mixture was diluted with AcOEt, filteredthrough a pad of celite and the filtrate was washed with water. Thecombined organic layers were dried over Na₂SO₄ and concentrated in vacuoto yield intermediate compound 31 (4.5 g, quant.) used in the nextreaction step without further purification.

A32. Intermediate Compound 32

To a mixture of(N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acidpinacol ester ([286961-14-6] CAS) (1.5 g, 4.8 mmol) in a mixture of1,4-dioxane (8 ml) and DMF (2 ml) were added 4-chloro-2-picoline (0.308g, 2.4 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, DCM (0.293 g, 0.36 mmol) and potassium carbonate (0.993 g,7.2 mmol). The mixture was then degassed using a stream of nitrogen andthen microwaved at 160° C. for 90 min. The cooled reaction mixture wasfiltered through a pad of celite and the filtrate was concentrated invacuo. The residue was purified by flash chromatography (SiO₂,DCM/MeOH(NH₃) mixtures) to yield intermediate compound 32 (0.5 g, 38%).

A33. Intermediate Compound 33

A solution of intermediate compound 32 (0.5 g, 1.82 mmol) in a 20%solution of TFA in DCM (10 ml) was stirred at room temperature for 4hours, after which time the solvent was evaporated. The residue (0.5 g)was used in the next reaction step without further purification.

A35. Intermediate Compound 35

To a solution of intermediate compound 2′ (1.5 g, 7.8 mmol) inacetonitrile (13 ml), (4-bromomethylphenyl)boronic acid, pinacol ester(3.0 g, 9.76 mmol) ([138500-85-3] CAS) and cesium carbonate (5.92 g,15.6 mmol) were added. The reaction mixture was microwaved at 160° C.for 30 min. Then, solvents were evaporated in vacuo and the residue waspurified by flash chromatography (SiO₂, DCM/MeOH mixtures) to yieldintermediate compound 35 (2.93 g, 92%).

A36. Intermediate Compound 36

A mixture of intermediate compound 3 (0.366 g, 1.361 mmol),

(compound described in US 2005187277 A1) (0.436 g, 1.63 mmol, Pd(PPh₃)₄(0.157 g, 0.136 mmol) in 1,4-dioxane (2 ml) and a saturated solution ofNa₂CO₃ (2 ml) was microwaved at 150° C. for 10 min. The resultingreaction mixture was then filtered through a pad of celite and thefiltrate evaporated in vacuum. The residue was subsequently purified byflash chromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yieldintermediate compound 36 (0.55 g, 98%).A39. Intermediate Compound 39

To a solution of 4-aminomethylphenylboronic acid, pinacol ester (CAS138500-88-6) (1.2 g, 5.14 mmol) and Et₃N (1.42 ml, 10.28 mmol) in DCM(50 ml) stirred at room temperature, di-tert-butyldicarbonate (1.68 g,7.72 mmol) was added. The mixture was stirred at room temperature for 2hours. The solvent was evaporated in vacuum to yield a residue which wastreated with diethylether to yield intermediate compound 39 (1.7 g) as asolid, 99%) used in the next reaction step without further purification.

A40. Intermediate Compound 40

To a solution of intermediate compound 39 (1.7 g, 5.14 mmol) in1,4-dioxane (3 ml) and a saturated solution of NaCO₃ (3 ml) was addedintermediate compound 3 (1.15 g, 4.28 mmol). The resulting solution wasdegassed using a stream of nitrogen and to this was added Pd(PPh₃)₄(485.0 mg, 0.42 mmol). The reaction was then microwaved into a sealedtube at 150° C. for 10 min. The resulting reaction mixture was thenfiltered through a pad of celite and the filtrate concentrated in vacuo.The crude reaction mixture was then purified by flash chromatography(SiO₂, DCM/McOH(NH₃) 9:1) to yield intermediate compound 40 (1.3 g,77%).

A41. Intermediate Compound 41

To a solution of intermediate compound 40 (0.125 g, 0.316 mmol) in DMF(dried, 5 ml) at 0° C., NaH (60% mineral oil; 0.019 mg, 0.474 mmol) wasadded. The resulting suspension was stirred at 0° C. (under nitrogenatmosphere) for 30 min. Then, 3-fluorobenzylbromide (0.059 ml, 0.474mmol) was added. The reaction mixture was stirred at room temperaturefor 3 hours. Then, water was added and the resulting aqueous mixture wasextracted with AcOEt. The organic layer was washed with a saturatedsolution of NaCl. The combined organic layers were dried over Na₂SO₄.The crude reaction mixture was then purified by flash chromatography(SiO₂, DCM/MeOH(NH₃) 9:1) to yield intermediate compound 41 (0.082 g,51%) as a yellow oil.

A42. Intermediate Compound 42

To a mixture of 4-bromo-2-fluoroaniline (0.6 g, 3.15 mmol),tetrahydro-4H-pyran-4-one (0.68 g, 6.31 mmol) and NaBH(OAc)₃ (0.96 g,4.72 mmol) in DCE (20 ml), molecular sieves (4A) (1 g) were added. Themixture was stirred at room temperature for 16 h. Then, additionalamounts of tetrahydro-4H-pyran-4-one (0.34 g, 3.15 mmol) and NaBH(OAc)₃(0.66 g, 3.15 mmol) were added and the mixture was stirred at roomtemperature for 48 h. Then, the reaction mixture was filtered through apad of celite and washed with DCM. The filtrate was concentrated invacuo to yield intermediate compound 42 (0.86 g, quant.) used in thenext reaction step without further purification.

A43. Intermediate Compound 43

To a solution of intermediate compound 42 (0.86 g, 3.15 mmol) in DMSO (3ml) was added bis(pinacolato)diboron (0.80 g, 3.15 mmol) and KOAc (0.93g, 9.45 mmol) the solution was then degassed using a stream of nitrogenand then to the reaction mixture was added1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.07g, 0.09 mmol). The reaction mixture was then heated at 120° C. under anitrogen atmosphere for 16 hours. The reaction was then cooled to roomtemperature and diluted with water (50 ml) and the resulting solutionwas extracted with AcOEt, the organic fraction was then dried overNa₂SO₄ and concentrated in vacuo to yield intermediate compound 43 (1.01g, 100%) used in the next reaction step without further purification.

A44. Intermediate Compound 44

To a solution of NaH (60% in mineral oil) (0.13 g, 3.25 mmol) in DMF (5ml) was added commercially available 4-bromophenol (0.50 g, 2.89 mmol)and the reaction was stirred at room temperature for 10 min. Then,4-chloro-2-picoline (0.30 g, 2.40 mmol) was added and the resultingreaction mixture was then microwaved at 150° C. for 10 min. Aftercooling, the mixture was diluted with water and extracted with Et₂O. Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The residue thus obtained was purified by flash chromatography(DCM) to yield intermediate compound 44 (0.52 g, 81%).

A45. Intermediate Compound 45

To a solution of intermediate compound 44 (0.50 g, 1.89 mmol) in DMSO (5ml) was added bis(pinacolato)diboron (0.72 g, 2.84 mmol) and KOAc (0.56g, 5.68 mmol) the solution was then degassed using a stream of nitrogenand then to the reaction mixture was added1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride, DCM (0.05g, 0.06 mmol). The reaction mixture was then heated at 110° C. under anitrogen atmosphere for 16 hours. The reaction was then cooled to roomtemperature and diluted with water and the resulting solution wasextracted with AcOEt, the organic fraction was then dried over Na₂SO₄and concentrated in vacuo to yield intermediate compound 45 (0.58 g,100%) used in the next reaction step without further purification.

B. Preparation of the Final Compounds

B1. Final Compound 1-110

To a solution of 3,4-dimethoxyphenylboronic acid (740.0 mg, 4.08 mmol)in 1,4-dioxane (14 ml) and a saturated solution of NaHCO₃ (14 ml) wasadded intermediate compound 3 (1.00 g, 3.70 mmol). The resultingsolution was degassed using a stream of nitrogen and to this was addedPd(PPh)₄ (641.0 mg, 0.55 mmol). The reaction was then microwaved into asealed tube at 150° C. for 10 min. The resulting reaction mixture wasthen filtered through a pad of celite and the filtrate concentrated invacuo. The crude reaction mixture was then purified by flashchromatography (eluting with a solvent gradient 0-2% MeOH in DCM) toyield the desired compound. The compound was then recrystallised fromdiethylether to yield the final compound 1-110 (940.0 mg, 2.88 mmol,78%).

B2. Final Compound 1-179

Intermediate compound 4 (150 mg, 0.44 mmol), and4-(acetamidomethyl)phenylboronic acid (129 mg, 0.67 mmol) were mixed in1,4-dioxane (5 ml) and Et₃N (0.12 ml, 0.89 mmol) at room temperature andN₂ was flushed through the mixture for 5 min. Pd(PPh₃)₄ (77 mg, 0.067mmol) was added and the resulting mixture was heated at 90° C. for 2hours. The mixture was cooled to room temperature, diluted with AcOEtand brine. The aqueous phase was extracted with AcOEt (3×20 ml). Thecombined organics layers were dried over Na₂SO₄, evaporated in vacuumand the residue thus obtained was purified by column chromatography(SiO₂, DCM/AcOEt) to yield 16 mg of final compound 1-179 as a whitesolid.

B3. Final Compound 1-114

Intermediate compound 4 (150 mg, 0.44 mmol),3-fluoro-4-methoxyphenylboronic acid (110 mg, 0.67 mmol) were mixed in1,4-dioxane (5 ml) and Et₃N (0.12 ml, 0.89 mmol) at room temperature andN₂ was flushed through the mixture for 5 min. Pd(PPh₃)₄ (77 mg, 0.067mmol) was added and the resulting mixture was heated at 90° C. for 2hours. The mixture was cooled to room temperature, diluted with AcOEtand brine. The aqueous phase was extracted with AcOEt (3×20 ml). Thecombined organics layers were dried over Na₂SO₄, evaporated in vacuumand the residue thus obtained was purified by column chromatography(SiO₂, DCM/AcOEt) to yield 43 mg of final compound 1-114 as a yellowsolid.

B4. Final Compound 1-095

Intermediate compound 4 (150 mg, 0.44 mmol) and4-(3-hydroxypropyl)-phenylboronic acid (120 mg, 0.67 mmol) were mixed in1,4-dioxane (5 ml) and Et₃N (0.12 ml, 0.89 mmol) at room temperature andN₂ was flushed through the mixture for 5 min. Pd(PPh₃)₄ (77 mg, 0.067mmol) was added and the resulting mixture was heated at 90° C. for 2hours. The mixture was cooled to room temperature, diluted with AcOEtand brine. The aqueous phase was extracted with AcOEt (3×20 ml). Thecombined organics layers were dried over Na₂SO₄, evaporated in vacuumand the residue thus obtained was purified by column chromatography(SiO₂, DCM/AcOEt) to yield 40 mg of final compound 1-095 as a whitesolid.

B5. Final Compound 1-103

Intermediate compound 4 (150 mg, 0.44 mmol),4-(methoxymethyl)phenylboronic acid (110 mg, 0.67 mmol) were mixed in1,4-dioxane (5 ml) and Et₃N (0.12 ml, 0.89 mmol) at room temperature andN₂ was flushed through the mixture for 5 min. Pd(PPh₃)₄ (77 mg, 0.067mmol) was added and the resulting mixture was heated at 90° C. for 2hours. The mixture was cooled to room temperature, diluted with AcOEtand brine. The aqueous phase was extracted with AcOEt (3×20 ml). Thecombined organics layers were dried over Na₂SO₄, evaporated in vacuumand the residue thus obtained was purified by column chromatography(SiO₂, DCM/AcOEt) to yield 52 mg of final compound 1-103 as a whitesolid.

B6. Final Compound 1-178

To a solution of intermediate compound 7 (220.0 mg, 0.58 mmol), in1,4-dioxane (6 ml) and a saturated solution of Na₂CO₃ (6 ml) was addedintermediate compound 3 (173 mg, 0.65 mmol). The resulting solution wasdegassed using a stream of nitrogen and to this was added Pd(PPh₃)₄(101.0 mg, 0.088 mmol). The reaction was then microwaved at 150° C. for10 min. The resulting reaction mixture was then filtered through a padof celite and the filtrate concentrated in vacuo. The crude reactionmixture was then purified by preparative HPLC to yield the pure finalcompound 1-178 (51 mg, 0.15 mmol, 26%).

B7. Final Compound 1-097

To a solution of 4-hydroxyphenylboronic acid (336 mg, 2.44 mmol), in1,4-dioxane (20 ml) and a saturated solution of NEt₃ (0.615 ml, 4.43mmol) was added final compound 5-052 (750 mg, 1.79 mmol). The resultingsolution was degassed using a stream of nitrogen and to this was addedPd(PPh₃)₄ (384 mg, 0.33 mmol). The reaction was heated at 90° C. for 2hours into a sealed tube. The resulting reaction mixture cooled to roomtemperature, was diluted with water and brine and extracted with AcOEt.The organic layer was dried over Na₂SO₄ and vacuum concentrated. Thecrude reaction mixture was then purified by flash chromatography (SiO₂,eluting with mixtures of heptane/AcOEt) to yield the final compound1-097 (230 mg, 45%).

B8. Final Compound 1-274

To a solution of phenol (0.042 ml, 0.48 mmol) in dry THF (3 ml) at roomtemperature, NaH (60% in mineral oil, 13.83 mg, 0.96 mmol) was added.The resulting mixture was stirred at room temperature for 5 min. Finalcompound 5-052 (100 mg, 0.24 mmol) was added. The mixture was microwavedinto a scaled tube for 10 min at 80° C. The mixture was cooled to roomtemperature, solvents were evaporated in vacuo and the residue thusobtained was purified by column chromatography (SiO₂, DCM/MeOH(NH₃)mixtures) to yield 55 mg of final compound 1-274 as a white solid.

B9. Final Compound 1-298

Intermediate compound 3 (100 mg, 0.371 mmol), aniline (0.067 ml, 0.743mmol) K₃PO₄ (158 mg, 0.745 mmol) and catalyst [577971-19-8] CAS (10 mg)were mixed in 1,4-dioxane (15 ml) at room temperature. The correspondingmixture was stirred at 80° C. (oil bath temperature) into a sealed tubefor 12 hours. The mixture was cooled to room temperature and AcOEt (30ml) and NaHCO₃ (10 ml, aqueous saturated solution) were added to thereaction mixture. Layers were separated and the organic one was driedover Na₂SO₄. Solvents were evaporated in vacuum and the residue thusobtained was purified by flash chromatography to yield final compound1-298 (50 mg).

B10. Final Compound 1-267

Reaction under nitrogen atmosphere. Intermediate compound 3 (150 mg,0.557 mmol), phenylacetylene (0.064 ml, 0.580 mmol), PdCl₂(PPh₃)₂ (19.6mg, 0.028 mmol) PPh₃ (3.7 mg, 0.014 mmol) and NEt₃ (0.078 ml, 2.23 mmol)were mixed in THF (6 ml) at room temperature and N₂ was flushed throughthe mixture for 5 min. CuI (1.3 mg, 0.007 mmol) was added and theresulting mixture was heated at 90° C. (oil bath temperature) into asealed tube for 10 hours. The reaction mixture was cooled to roomtemperature and aqueous Na₂S₂O₄ (saturated solution) was added. DCM (30ml) was added and the layers were separated. The organic layer waswashed with aqueous NaHCO₃ (saturated solution), dried over Na₂SO₄ andvacuum concentrated. The residue thus obtained was purified by flashchromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yield final compound1-267 (57 mg).

B11. Final Compound 1-260

10% Pd/C (10 mg) was added to a solution of final compound 1-267 (45 mg,0.155 mmol) and 1,4-cyclohexadiene (0.22 ml, 2.32 mmol) in MeOH (5 ml)at room temperature. The resulting mixture was stirred into a sealedtube for 12 hours. The catalyst was filtered off and solvents wereevaporated in vacuo. The residue thus obtained was taken up in MeOH (15ml) and 10% Pd/C (10 mg) was added. The resulting mixture washydrogenated with hydrogen (20 psi) for 3 hours. The catalyst wasfiltered off and the solvent was evaporated. The residue thus obtainedwas purified by flash chromatography (SiO₂, DCM/McOH(NH₃) mixtures) andthen by reverse phase HPLC chromatography to yield final compound 1-260as a white solid (1.63 mg).B12. Final Compound 1-182

To a solution of intermediate compound 8 (80 mg, 0.62 mmol), in1,4-dioxane (1 ml) and a saturated solution of Na₂CO₃ (1 ml) was addedintermediate compound 3 (64.34 mg, 0.239 mmol). The resulting solutionwas degassed using a stream of nitrogen and to this solution was addedPd(PPh₃)₄ (41.4 mg, 0.035 mmol). The reaction was then microwaved at140° C. for 5 min. The resulting reaction mixture was subsequentlyfiltered through a pad of celite and AcOEt (10 ml) was added. H₂O (10ml) was added and layers were separated. The organic layers were dried(Mg₂SO₄) and vacuum concentrated. The resulting residue was thenpurified by column chromatography (SiO₂, DCM/MeOH(NH₃) mixtures) toyield the pure final compound 1-182 (28 mg) as bright yellow solid.

B13. Final Compound 1-258

To a solution of intermediate compound 9 (121 mg, 0.371 mmol), in1,4-dioxane (3 ml) and a saturated solution of NaHCO₃ (3 ml) was addedintermediate compound 3 (100 g, 3.71 mmol). The resulting solution wasdegassed using a stream of nitrogen and to this was added Pd(PPh₃)₄(64.0 mg, 0.056 mmol). The reaction was then microwaved at 150° C. for10 min. The resulting reaction mixture was then filtered through a padof celite and the filtrate concentrated in vacuo. The crude reactionmixture was then purified by HPLC purification to yield final compound1-258 (13.0 mg, 0.034 mmol, 10%).

B14. Final Compound 1-239

Intermediate compound 4 (150 mg, 0.44 mmol) and4-(methyl-3-propanoate)phenylboronic acid (140 mg, 0.67 mmol) were mixedin 1,4-dioxane (5 ml) and Et₃N (0.12 ml, 0.89 mmol) at room temperature,and N₂ was flushed through the mixture for 5 min. Pd(PPh₃)₄ (77 mg, 0.06mmol) was added to the mixture and the resulting mixture was heated at90° C. for 2 hours. The mixture was cooled to room temperature, dilutedwith AcOEt and brine. The aqueous phase was extracted with AcOEt (3×20ml). The combined organics layers were dried over Na₂SO₄, evaporated invacuum and the residue thus obtained was purified by columnchromatography (SiO₂, DCM/AcOEt) to yield 63 mg of final compound 1-239as a yellow solid.

B15. Final Compound 1-240

To a solution of final compound 1-239 (20 mg, 0.057 mmol) in THF/H₂O 1:1(4 ml) at 0° C. was added lithium hydroxide (24 mg, 0.57 mmol). Thereaction mixture was stirred for 30 min and the solution wasconcentrated. The pH was adjusted to pH=2 with a 1 N solution of HCl andthe precipite thus formed was filtered off and dried, to yield 10 mg ofthe final compound 1-240 as a white solid.

B16. Final Compound 2-043

Intermediate compound 12 (300 mg, 0.804 mmol),1-(2-phenylethyl)piperazine (0.176 ml, 0.964 mmol) K₃PO₄ (341 mg, 1.60mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane(6 ml) at room temperature. The corresponding mixture was heated at 110°C. into a sealed tube for 16 hours. The mixture was cooled to roomtemperature, filtered through a pad of celite and washed with AcOEt. Thefiltrate was concentrated in vacuo and the residue thus obtained waspurified by flash chromatography to yield final compound 2-043 as a paleyellow solid (349 mg, 90%).

B17. Final Compound 1-037

Intermediate compound 12 (350 mg, 0.938 mmol) and intermediate compound13 (375 mg, 1.12 mmol) were mixed in 1,4-dioxane (3 ml) and a saturatedsolution of Na₂CO₃ (3 ml). The resulting solution was degassed using astream of nitrogen and to this was added Pd(PPh₃)₄ (108.3 mg, 0.093mmol). The reaction was then microwaved into a sealed tube at 150° C.for 10 min. The resulting reaction mixture was then filtered through apad of celite and washed with AcOEt. The filtrate was concentrated invacuo and the residue thus obtained was purified by flash chromatographyto yield the final compound 1-037 (305.6 mg, 65%).

B18. Final Compound 2-022

A mixture of final compound 2-056 (150 mg, 0.55 mmol),3-chloro-4-(trifluoromethoxy)benzyl bromide (0.16 ml, 0.55 mmol) andK₂CO₃ (150 mg, 1.1 mmol) in DMF (2 ml) was stirred overnight at roomtemperature. The resulting reaction mixture was then filtered through apad of celite and washed with AcOEt. The filtrate was concentrated invacuo and the residue thus obtained was purified by flash chromatographyto yield the desired compound. The compound was then recrystallised fromdiethylether to yield the final compound 2-022 (170 mg, 64%).

B19. Final Compound 1-250

Intermediate compound 3 (198 mg, 0.74 mmol) and intermediate compound 16(200 mg, 0.74 mmol) were mixed in 1,4-dioxane (5 ml) and a saturatedsolution of Na₂CO₃ (5 ml). The resulting solution was degassed using astream of nitrogen and to this was added Pd(PPh₃)₄ (128 mg, 0.115 mmol).The reaction was then microwaved into a sealed tube at 150° C. for 10min. The resulting reaction mixture was then filtered through a pad ofcelite and washed with AcOEt. The filtrate was concentrated in vacuo andthe residue thus obtained was purified by flash chromatography to yieldthe final compound 1-250 (63.9 mg, 26%, yield based on two subsequentreaction steps).

B20. Final Compound 1-223

Intermediate compound 3 (727 mg, 2.70 mmol) and commercially available4-(morpholino)phenylboronic acid (560 mg, 2.70 mmol) were mixed in1,4-dioxane (10 ml) and a saturated solution of Na₂CO₃ (10 ml). Theresulting solution was degassed using a stream of nitrogen and to thiswas added Pd(PPh₃)₄ (468 mg, 0.405 mmol). The reaction was thenmicrowaved into a sealed tube at 150° C. for 10 min. The resultingreaction mixture was then filtered through a pad of celite and thefiltrate was washed with water (10 ml). The combined organic layers weredried over Na₂SO₄ and evaporated in vacuum. The crude reaction mixturewas subsequently purified by flash chromatography to yield the desiredcompound. The compound was then recrystallised from ethylether to yieldthe final compound 1-223 (620 mg, 65%).

B21. Final Compound 1-049

Intermediate compound 19 (250 mg, 0.783 mmol) and3-chloro-4-isopropoxy-phenylboronic acid (159 mg, 0.86 mmol) were mixedin 1,4-dioxane (2.5 ml) and a saturated solution of NaHCO₃ (2.5 ml). Theresulting solution was degassed using a stream of nitrogen and to thiswas added Pd(PPh₃)₄ (130 mg, 0.11 mmol). The reaction was thenmicrowaved into a sealed tube at 150° C. for 10 min. The resultingreaction mixture was then filtered through a pad of celite and thefiltrate evaporated in vacuum. The crude reaction mixture wassubsequently purified by flash chromatography to yield the desiredcompound. The compound was then recrystallised from diethylether toyield the final compound 1-049 as a white solid (65 mg, 21%).

B22. Final Compound 4-020

Intermediate compound 3 (100 mg, 0.37 mmol),4-(3-trifluoromethylbenzyloxy)-piperidine (115.11 mg, 0.444 mmol), K₃PO₄(150 mg, 0.70 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in1,4-dioxane (5 ml) at room temperature. The corresponding mixture washeated at 85° C. into a scaled tube for 16 hours. The mixture was cooledto room temperature and filtered through a pad of celite. The filtratewas concentrated in vacuo and the residue thus obtained was purified byflash chromatography to yield final compound 4-020 as a white gummysolid (90 mg, 55%).

B23. Final Compound 4-044

Intermediate compound 3 (150 mg, 0.406 mmol),4,4-(phenylpiperidin-4-yl)-morpholine (113.3 mg, 0.46 mmol), K₃PO₄ (200mg, 0.94 mmol) and catalyst [577971-19-8] CAS (10 mg) were mixed in1,4-dioxane (4 ml) at room temperature. The corresponding mixture washeated at 85° C. into a sealed tube for 36 hours. The mixture was cooledto room temperature and filtered through a pad of celite. The filtratewas concentrated in vacuo and the residue thus obtained was purified byprep. HPLC to yield final compound 4-044 as pale yellow solid (123 mg,51%).

B24. Final Compound 2-028

Intermediate compound 3 (226 mg, 0.84 mmol), 1-(2-pyrimidyl)piperazinedihydrochloride (228 mg, 0.96 mmol), K₃PO₄ (612 mg, 2.88 mmol) andcatalyst [577971-19-8] CAS (10 mg) were mixed in 1,4-dioxane (5 ml) atroom temperature. The corresponding mixture was heated at 85° C. into asealed tube for 36 hours. The mixture was cooled to room temperature andfiltered through a pad of celite. The filtrate was concentrated in vacuoand the residue thus obtained was purified by flash chromatography toyield final compound 2-028 as a pale creamy solid (258 mg, 87%).

B25. Final Compound 3-009

A mixture of intermediate compound 20 (0.223 g, 0.00081 mol, 1.1 eq.)and NaH (60% dispersion in mineral oil, 0.035 g, 0.00088 mol, 1.2 eq.)in DME (1.5 ml) was stirred at room temperature over 10 min. Then,intermediate compound 3 (0.20 g, 0.00074 mol, 1 eq.) was added slowly.The resulting reaction mixture was microwaved at 130° C. for 20 min. Themixture was cooled to room temperature and solvents were evaporated invacuum. The residue was suspended in DCM, filtered off and the filtrateconcentrated in vacuo. The crude reaction mixture was then purified byflash chromatography to yield final compound 3-009 (146 mg, 47%).

B26. Final Compound 3-008

To a solution of final compound 3-016 (346 mg, 1.19 mmol) and3-(trifluoromethyl)benzaldehyde ([454-89-7] CAS) (262 mg, 1.5 mmol) inDCE (40 ml), NaBH(OAc)₃ (760 mg, 3.6 mmol) was added portionwise. Thereaction mixture was stirred at room temperature for 3 hours. Then, themixture was quenched with an aqueous solution of NH₄Cl. The combinedorganic layers were concentrated in vacuo. The crude product waspurified by flash chromatography to yield final compound 3-008 (370 mg)as a pale brown solid.

B27. Final Compound 1-271

To a mixture of intermediate compound 11 (200 mg, 0.64 mmol),intermediate compound 24 (267 mg, 1.28 mmol) and PPh₃ (309 mg, 1.15mmol) in THF (5 ml) was added di-tert-butylazodicarboxylate (279 mg,1.21 mmol). The reaction mixture was microwaved at 120° C. over 20 min.The reaction mixture was then cooled to room temperature andconcentrated in vacuo. The residue was purified by flash chromatography(eluting with a solvent gradient 10-20% DCM/MeOH(NH₃) to give the finalcompound 1-271 (219.7 mg, 70%).

B28. Final Compound 3-014

To a solution of final compound 3-018 (191 mg, 0.70 mmol) and3-(trifluoromethyl)benzaldehyde ([454-89-7] CAS) (174 mg, 1 mmol) in DCE(16 ml), NaBH(OAc)₃ (443 mg, 2.1 mmol) was added portionwise. Themixture was stirred at room temperature for 3 hours, after which time itwas quenched with a saturated solution of NH₄Cl. The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by flash chromatography to yield final compound3-014 as white solid (270 mg, 89%).

B29. Final Compound 2-036

To a mixture of intermediate compound 2 (0.2 g, 0.971 mmol), K₂CO₃(0.268 g, 1.942 mmol) and NaI (cat.) in acetonitrile (12 ml),1-(2-chloroethyl)-4-pyridin-2-yl-piperazine (0.393 g, 1.748 mmol) wasadded. The reaction mixture was microwaved twice at 150° C. for 10 min.Then, DCM was added and the mixture was filtered off. The filtrate waswashed with a saturated solution of NaHCO₃. The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (DCM/MeOH(NH₃) mixtures) to give finalcompound 2-036 (152.5 mg, 40%) as off white solid.

B30. Final Compound 5-007

To a solution of intermediate compound 28 (35 mg, 0.161 mmol) in DCM (6ml) a drop of TFA was added. Then,N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (46 mg, 0.193mmol) was slowly added and the resulting reaction mixture was stirred atroom temperature for 2 hours. Then, solvents were evaporated in vacuumand the residue was purified by flash chromatography (SiO₂,DCM/MeOH(NH₃) mixtures) to yield final compound 1-131 (6 mg, 10%).

B31. Final Compound 2-055

A mixture of intermediate compound 12′ (250 mg, 0.81 mmol),1-(2-pyridyl)-piperazine (0.129 ml, 0.85 mmol) and diisopropylethylamine(0.416 ml, 2.4 mmol) in acetonitrile (5 ml) was microwaved at 160° C.for 30 min. The mixture was cooled to room temperature and the solventswere evaporated in vacuum. The residue thus obtained was purified byflash chromatography (SiO₂, DCM/MeOH mixtures) to yield final compound2-055 (192 mg, 61%) as a white solid.

B32. Final Compound 5-020

Intermediate compound 3 (0.6 g, 2.20 mmol) and intermediate compound 31(3.69 g, 3.79 mmol) were mixed in 1,4-dioxane (7 ml) and a saturatedsolution of Na₂CO₃ (6 ml). The resulting solution was degassed using astream of nitrogen and to this was added Pd(PPh₃)₄ (0.39 g, 0.33 mmol).The reaction was then microwaved into a sealed tube at 140° C. for 5min. The resulting reaction mixture was then diluted with AcOEt,filtered through a pad of celite and the filtrate was washed with water(10 ml). The combined organic layers were dried over Na₂SO₄ andevaporated in vacuum. The crude reaction mixture was subsequentlypurified by flash chromatography to yield the desired compound. Thecompound was then recrystallised from diethylether to yield the finalcompound 5-020 (0.39 g, 44%).

B33. Final Compound 4-047

A mixture of intermediate compound 3″ (0.3 g, 1.18 mmol),4-phenylpiperidine (0.286 g, 1.77 mmol) and diisopropylethylamine (0.615ml, 3.54 mmol) in acetonitrile (5 ml) was microwaved at 150° C. for 20min. The mixture was cooled to room temperature and the solvents wereevaporated in vacuum. The residue thus obtained was purified by flashchromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yield the desiredcompound. The compound was then recrystallised from ethylether to yieldthe final compound 4-047 (0.29 g, 73%)

B34. Final Compound 4-003

A mixture of final compound 5-054 (0.37 g, 1.05 mmol) and palladium (10%on activated carbon) (catalytic amount) in EtOH (10 ml) was stirredunder a hydrogen atmosphere at 50 psi for 3 hours. The catalyst was thenfiltered off and the filtrate was concentrated in vacuo. The residuethus obtained was purified by flash chromatography (SiO₂, DCM/MeOH(NH₃)mixtures) to yield final compound 4-003 (0.21 g, 57%).

B35. Final Compound 1-306

Intermediate compound 35 (0.25 g, 0.61 mmol) and commercially available2-bromo-6-methylpyridine (0.158 g, 0.92 mmol) were mixed in 1,4-dioxane(2 ml) and a saturated solution of NaHCO₃ (2 ml). The resulting solutionwas degassed using a stream of nitrogen and to this was added Pd(PPh₃)₄(0.10 g, 0.09 mmol). The reaction was then microwaved into a sealed tubeat 150° C. for 10 min. The resulting reaction mixture was then filteredthrough a pad of celite and the filtrate was washed with water (10 ml).The combined organic layers were dried over Na₂SO₄ and evaporated invacuum. The crude reaction mixture was subsequently purified by flashchromatography to yield final compound 1-306 (0.078 g, 34%).

B36. Final Compound 5-015

To a solution of final compound 5-014 (0.04 g, 0.130 mmol), prepared bythe reaction pathway B1, and diisopropylethylamine (0.068 ml, 0.392mmol) in DCM (2 ml), acetyl chloride (0.014 ml, 0.196 mmol) was added.The reaction mixture was stirred at room temperature for 12 hours. Then,the solvents were evaporated in vacuum and the residue thus obtained waspurified by flash chromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yieldfinal compound 5-015 (0.045 g, 99%).

B37. Final Compound 1-198

To a solution of intermediate compound 41 (0.082 mg. 0.163 mmol) in DCM(10 ml), TFA (5 ml) was added. The resulting solution was stirred atroom temperature for 3 hours. Then, solvent was evaporated in vacuo andthe residue was dissolved in DCM, washed with a saturated solution ofNaHCO₃ and NaCl. The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo The residue was purified by flash chromatography(DCM/MeOH(NH₃) mixtures) to give final compound 1-198 (17 mg, 26%) as awhite solid.

B38. Final Compound 1-185

To a mixture of final compound 1-308 (0.2 g, 0.533 mmol) in 1,4-dioxane(10 ml), N-methyl-2-methoxyethylamine (0.0711 mg, 0.8 mmol), Paladiumdiacetate (0.0118 mg, 0.053 mmol) and Xantphos (0.0616 mg, 0.8 mmol)were added. The reaction mixture was stirred in a sealed tube at 120° C.for 16 hours. The resulting reaction mixture was then filtered through apad of celite, washed with AcOEt. The filtrate was washed with asaturated solution of NaCl. The combined organic layers were dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (DCM/MeOH 9:1) to give final compound 1-185 (24 mg, 12%)as a yellow solid.

B39. Final Compound 1-226

To a solution of final compound 1-224 (0.147 mg, 0.385 mmol) in DCM (20ml) at 0° C., BBr₃ (0.182 ml, 1.92 mmol) was added. The resultingsolution was warmed up to room temperature and stirred for 16 hours.Then, an aqueous solution of NH₄OH was added. The resulting aqueoussolution was extracted with methylenehlorine, washed with a saturatedsolution of NaCl. The combined organic layers were dried over MgSO₄ andconcentrated in vacuo The residue was purified by flash chromatography(DCM/MeOH(NH₃) 9:1) to give final compound 1-226 (28 mg, 20%) as yellowsolid.

B40. Final Compound 5-052

The reaction was carried out under N₂ atmosphere. Intermediate compound4 (26 mg, 0.077 mmol) was dissolved in pyridine (1 ml, 12.26 mmol). Theresulting solution was heated for 1 hour at 40° C. The mixture wascooled to room temperature and solvents were evaporated in vacuum. Theresidue thus obtained was treated with 1,4-dioxane to yield a whitesolid that was filtered off, dried in vacuum and identified as finalcompound 5-052 (25 mg; white solid).

B41. Final Compound 2-056

A solution of intermediate compound 14 (200 mg, 0.53 mmol) in a mixtureof TFA/DCM (20%) (5 ml) was stirred overnight at room temperature. Themixture was basified by the addition of K₂CO₃ (saturated solution). Theorganic layer was then dried over MgSO₄ and concentrated in vacuo. Theresidue was identified as final compound 2-056 (150 mg) and was used inthe next reaction step without further purification.

B42. Final Compound 3-015

To a mixture of 1-tert-butoxycarbonyl-4-hydroxypiperidine (447 mg, 2.22mmol) in DME (8 ml), NaH (60% in mineral oil) was added and the reactionmixture was stirred at room temperature for 5 min. Then, intermediatecompound 3 (500 mg, 1.85 mmol) was added and the resulting reactionmixture was microwaved at 130° C. for 30 min. The reaction was thencooled to room temperature and filtered off. The filtrate wasconcentrated in vacuo to yield final compound 3-015 as brown oil (460mg).

B43. Final Compound 3-016

To a solution of final compound 3-015 (460 mg, 1.18 mmol) in MeOH (50ml), amberlyst-15 polymer bound (loading 4.6 mmol/g) (0.77 g, 3.54 mmol)was added. The resulting mixture was shaken at room temperature for 12hours. Then, the resin was filtered off and the solvent was discarded.The resin was suspended in MeOH/NH₃ (50 ml) and shaken at roomtemperature for 3 hours. The resin was filtered off and the filtrate wasconcentrated in vacuo to give the final compound 3-016 (350 mg) as apale brown solid.

B44. Final Compound 5-053

A mixture of intermediate compound 3 (1 g, 3.71 mmol),(N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acidpinacol ester (1.26 g, 4.08 mmol) and Pd(PPh₃)₄ (0.642 g, 0.556 mmol) in1,4-dioxane (6 ml) and a saturated solution of Na—HCO₃ (6 ml) wasmicrowaved at 150° C. for 10 min. The resulting reaction mixture wasthen filtered through a pad of celite and the filtrate evaporated invacuum. The crude reaction mixture was subsequently purified by flashchromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yield final compound5-053 (0.57 g, 41%) as a white solid.

B45. Final Compound 3-017

A mixture of final compound 5-053 (530 mg, 1.42 mmol) and palladium (10%on activated carbon) (catalytic amount) in AcOEt (50 ml) was stirredunder a hydrogen atmosphere at 50 psi for 4 hours. The catalyst was thenfiltered off and the filtrate was concentrated in vacuo to give finalcompound 3-017 as colorless oil (540 mg, quant.). The compound thusobtained was used in the next reaction steps without furtherpurification.

B46. Final Compound 3-018

To a solution of final compound 3-017 (540 mg, 1.44 mmol) in MeOH (50ml), amberlyst-15 (loading 4.6 mmol/g) (1 g, 4.6 mmol) was added. Theresulting mixture was shaken at room temperature for 12 hours. Then, theresin was filtered off and the solvent was discarded. The resin wassuspended in MeOH/NH₃ (50 ml) and shaken at room temperature for 3hours. The resin was filtered off and the filtrate was concentrated invacuo to yield final compound 3-018 (198 mg) as yellow oil.

B47. Final Compound 5-054

A mixture of intermediate compound 3′ (0.34 g, 1.33 mmol), intermediatecompound 33 (0.5 g, 1.73 mmol) and diisopropylethylamine (0.925 ml, 5.32mmol) in acetonitrile (3 ml) was microwaved at 150° C. for 20 min. Themixture was cooled to room temperature and the solvents were evaporatedin vacuum. The residue thus obtained was purified by flashchromatography (SiO₂, DCM/MeOH(NH₃) mixtures) to yield final compound5-054 (0.37 g, 79%).

B48. Final Compound 1-307

To a solution of intermediate compound 36 (0.55 mg. 1.76 mmol) in DCM(20 ml), TFA (10 ml) was added. The resulting solution was stirred atroom temperature for 2 hours. Then, solvent was evaporated in vacuo andthe residue was dissolved in DCM, washed with a saturated solution ofNaHCO₃ and NaCl. The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to yield final compound 1-307 (0.310 g, 74%) usedin the next reaction step without further purification.

B49. Final Compound 1-308

To a suspension of copper (II) bromide (0.2 g, 0.89 mmol) andtert-butylnitrite (0.178 ml, 1.48 mmol) in acetonitrile (29 ml) at 0° C.was added dropwise final compound 1-307 (0.31 g, 0.99 mmol) within 5 minat 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed toroom temperature and gradually heated at 65° C. for 1 hour. Theresulting reaction mixture was then filtered through a pad of celite,washed with acetonitrile and the filtrate evaporated in vacuum to yieldfinal compound 1-308 (0.464 g) used in the next reaction step withoutfurther purification.

B50. Final Compound 1-190

Intermediate compound 43 (0.30 g, 1.11 mmol) and intermediate compound 3(0.43 g, 1.33 mmol) were mixed in 1,4-dioxane (3 ml) and a saturatedsolution of Na₂CO₃ (3 ml). The resulting solution was degassed using astream of nitrogen and to this was added Pd(PPh₃)₄ (0.12 g, 0.1 mmol).The reaction was then microwaved into a sealed tube at 150° C. for 10min. The resulting reaction mixture was then filtered through a pad ofcelite and washed with AcOEt. The filtrate was washed with brine. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.The residue thus obtained was purified by prep. HPLC to yield finalcompound 1-190 (0.04 g, 9%).

B51. Final Compound 1-064

Intermediate compound 3 (0.48 g, 1.89 mmol) and intermediate compound 45(0.59 g, 1.89 mmol) were mixed in 1,4-dioxane (4 ml) and a saturatedsolution of NaHCO₃ (4 ml). The resulting solution was degassed using astream of nitrogen and to this was added Pd(PPh₃)₄ (0.22 g, 0.19 mmol).The reaction was then microwaved into a sealed tube at 150° C. for 10min. The resulting reaction mixture was then filtered through a pad ofcelite and washed with AcOEt. The filtrate was washed with brine. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.The residue thus obtained was purified by flash chromatography (DCM/MeOHmixtures) to yield final compound 1-064 (0.16 g, 25%).

The final compounds in the following Tables have been synthesisedaccording to the previous examples, as denoted in the column denoted as“Exp. Nr”. The compound denoted with the asterisk has been exemplifiedin the Examples.

TABLE 1A Compounds wherein L is a covalent bond.

Co. Exp nr. nr. V¹ M¹ - - - -L-A 1-001 B2 cb

1-002 B2 cb

1-003 B1 - - - -CH₂- - - -

1-004 B3 - - - -CH₂- - - -

1-005 B3 - - - -CH₂- - - -

1-006 B3 - - - -CH₂- - - -

1-007 B1 - - - -CH₂- - - -

1-008 B2 - - - -CH₂- - - -

1-009 B2 - - - -CH₂- - - -

1-010 B1 - - - -CH₂- - - -

1-011 B1 - - - -CH₂- - - -

1-012 B1 - - - -CH₂- - - -

1-013 B1 - - - -CH₂- - - -

1-014 B1 - - - -CH₂- - - -

1-015 B2 - - - -CH₂- - - -

1-016 B1 - - - -CH₂- - - -

1-017 B1 - - - -CH₂- - - -

1-018 B2 - - - -CH₂- - - -

1-019 B2 - - - -CH₂- - - -

1-020 B2 - - - -CH₂- - - -

1-021 B1 - - - -CH₂- - - -

1-022 B1 - - - -CH₂- - - -

1-023 B2 - - - -CH₂- - - -

1-024 B1 - - - -CH₂- - - -

1-025 B1 - - - -CH₂- - - -

1-026 B1 - - - -CH₂- - - -

1-027 B1 - - - -CH₂- - - -

1-028 B2 - - - -CH₂- - - -

1-029 B2 - - - -CH₂- - - -

1-030 B1 - - - -CH₂- - - -

1-031 B1 - - - -CH₂- - - -

1-032 B1 - - - -CH₂- - - -

1-033 B1 - - - -CH₂- - - -

1-034 B1 - - - -CH₂- - - -

1-035 B1 - - - -CH₂- - - -

1-036 B1 - - - -CH₂- - - -

1-037 B17* - - - -CH₂- - - -

1-038 B1 - - - -CH₂- - - -

1-039 B1 - - - -CH₂- - - -

1-040 B1 - - - -CH₂- - - -

1-041 B1 - - - -CH₂- - - -

1-042 B1 - - - -CH₂- - - -

1-043 B2 - - - -CH₂- - - -

1-044 B1 - - - -CH₂- - - -

1-045 B1 - - - -CH₂- - - -

1-046 B2 - - - -CH₂- - - -

1-047 B2 - - - -CH₂—CH₂- - - -

1-048 B1 - - - -CH₂—CH₂- - - -

1-049 B21* - - - -CH₂—CH₂- - - -

1-050 B2 - - - -CH₂—CH₂—CH₂- - - - - - - -H

1-051 B2 - - - -CH₂—CH₂—CH₂- - - -

1-052 B2 - - - -CH₂—CH₂—CH₂- - - -

1-053 B1 - - - -CH₂—CH₂—CH₂- - - -

1-054 B2 - - - -CH₂—CH═CH- - - -

1-055 B1 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-056 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-057 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-058 B1 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-059 B2 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-060 B1 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-061 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-062 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-063 B1 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-064 B51* - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-065 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-066 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-067 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-068 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-069 B29 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-070 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-071 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-072 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-073 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-074 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-075 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-076 B3 - - - -CH₂—CH₂—CH₂—CH₂- - - - - - - -H

1-077 B2 - - - -CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-078 B3 - - - -CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-079 B2 - - - -CH(CH₃)—CH₂—CH₂—CH₂- - - - - - - -H

1-080 B2 - - - -CH₂—CH(CH₃)—CH₂—CH₂- - - - - - - -H

1-081 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-082 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-083 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-084 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-085 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-086 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-087 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-088 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-089 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-090 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-091 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-092 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-093 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-094 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-095 B4* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-096 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-097 B7* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-098 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-099 B37 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-100 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-101 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-102 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-103 B5* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-104 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-105 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-106 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-107 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-108 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-109 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-110 B1* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-111 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-112 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-113 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-114 B3* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-115 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-116 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-308 B49* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-117 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-118 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-119 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-120 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-121 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-122 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-123 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-124 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-125 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-126 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-127 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-128 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-129 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-130 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-131 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-132 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-133 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-134 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-135 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-136 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-137 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-138 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-139 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-140 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-141 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-142 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-143 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-144 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-145 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-146 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-147 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-148 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-149 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-150 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-151 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-152 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-153 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-154 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-155 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-156 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-157 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-158 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-159 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-160 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-161 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-162 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-163 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-164 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-165 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-166 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-167 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-168 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-169 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-170 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-305 B37 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-171 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-172 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-173 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-174 B37 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-307 B48* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-175 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-176 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-177 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-178 B6* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-179 B2* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-180 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-181 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-182 B12* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-183 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-184 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-185 B38* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-186 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-187 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-188 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-189 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-190 B50* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-191 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-192 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-193 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-194 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-195 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-196 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-197 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-198 B37* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-199 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-200 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-201 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-202 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-203 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-204 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-205 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-206 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-207 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-208 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-209 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-210 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-211 B28 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-212 B29 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-213 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-214 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-215 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-216 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-217 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-218 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-219 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-220 B9 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-221 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-222 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-223 B20* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-224 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-225 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-226 B39* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-227 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-228 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-229 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-230 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-231 B38 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-232 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-233 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-234 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-235 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-236 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-237 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-238 B2 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-239 B14* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-240 B15* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-241 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-242 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-243 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-244 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-245 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-246 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-247 B3 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-248 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-249 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-250 B19* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-251 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-252 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-253 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-254 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-255 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-256 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-257 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-258 B13* - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

1-259 B1 - - - -CH₂—CH₂—CH(CH₃)—CH₂- - - - - - - -H

TABLE 1B Compounds wherein L is a saturated or unsaturated alkyl chain.

Co. Exp nr. nr. V¹ M¹ —L—A 1-260 B11* —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-261 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-262 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-263 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-264 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-265 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-266 B11 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-267 B10* —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-268 B10 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-269 B10 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-270 B10 —CH₂—CH₂—CH(CH₃)—CH₂— —H

TABLE 1C Compounds wherein L contains an O-atom.

Co. Exp nr. nr. V¹ M¹ —L—A 1-271 B27* —CH₂—

1-272 B29 —CH₂—

1-273 B8 —CH₂—CH₂—CH₂—CH₂— —H

1-306 B35* —CH₂—CH₂—CH₂—CH₂— —H

1-274 B8* —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-275 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-276 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-277 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-278 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-279 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-280 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-281 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-282 B8 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-283 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-284 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-285 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-286 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-287 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-288 B27 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-289 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-290 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-291 B8 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-292 B27 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-293 B29 —CH₂—CH₂—CH(CH₃)—CH₂— —H

TABLE 1D Compounds wherein L contains a N-atom.

Co. Exp nr. nr. V¹ M¹ —L—A 1-294 B31 —CH₂—

1-295 B29 —CH₂—

1-296 B29 —CH₂—CH₂—CH₂—CH₂— —H

1-297 B31 —CH₂—CH₂—CH₂—CH₂— —H

1-298 B9* —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-299 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-300 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-301 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-302 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-303 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

1-304 B9 —CH₂—CH₂—CH(CH₃)—CH₂— —H

TABLE 2 Compounds prepared according to the Examples wherein A ispiperazinyl.

Co. Exp nr. nr. —V¹—M¹ —L— —R⁴ 2-001 B28 —CH₂—CH₂—CH₂—CH₃ cb

2-002 B18 —CH₂—CH₂—CH₂—CH₃ cb

2-003 B28 —CH₂—CH₂—CH₂—CH₃ cb

2-004 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-005 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-006 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-007 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-008 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-009 B33 —CH₂—CH₂—CH₂—CH₃ cb

2-010 B18 —CH₂CH(CH₃)₂ cb

2-056 B41* —CH₂—CH₂—CH(CH₃)₂ cb — 2-011 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-012 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-013 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-014 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-015 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-016 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-017 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-018 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-019 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-020 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-021 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-022 B33 —CH₂—CH₂—CH(CH₃)₂ cb

2-023 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-024 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-025 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-026 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-027 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-028 B24* —CH₂—CH₂—CH(CH₃)₂ cb

2-029 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-030 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-031 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-032 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-033 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-034 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-035 B23 —CH₂—CH₂—CH(CH₃)₂ cb

2-036 B29* —CH₂—CH₂—CH(CH₃)₂ —O(CH₂)₂—

2-037 B33 —CH₂—CH₂—CH(CH₃)₂ —(C═O)—

2-038 B28

cb

2-039 B28

cb

2-040 B28

cb

2-041 B33

cb

2-042 B23

cb

2-043 B16*

cb

2-044 B23

cb

2-045 B33

cb

2-046 B18

cb

2-047 B23

cb

2-048 B23

cb

2-049 B18*

cb

2-050 B18

cb

2-051 B18

cb

2-052 B18

cb

2-055 B31*

cb

2-053 B18

cb

2-054 B18

cb

TABLE 3 Compounds prepared according to the Examples wherein A is4-piperidinyl.

Co. Exp nr. nr. —V¹—M¹ —L— —R⁴ 3-001 B10 —CH₂—CH₂—CH₂—CH₃ cb

3-002 B18 —CH₂—CH₂—CH₂—CH₃ —O—

3-018 B46* —CH₂—CH₂—CH(CH₃)₂ cb — 3-017 B45* —CH₂—CH₂—CH(CH₃)₂ cb

3-014 B28* —CH₂—CH₂—CH(CH₃)₂ cb

3-003 B23 —CH₂—CH₂—CH(CH₃)₂ —NH—

3-004 B18 —CH₂—CH₂—CH(CH₃)₂ —NH—

3-005 B23 —CH₂—CH₂—CH(CH₃)₂ —N(CH₃)—

3-006 B23 —CH₂—CH₂—CH(CH₃)₂ —N(CH₃)—

3-016 B43* —CH₂—CH₂—CH(CH₃)₂ —O— — 3-007 B25 —CH₂—CH₂—CH(CH₃)₂ —O—

3-015 B42* —CH₂—CH₂—CH(CH₃)₂ —O—

3-008 B26* —CH₂—CH₂—CH(CH₃)₂ —O—

3-009 B25* —CH₂—CH₂—CH(CH₃)₂ —OCH₂—

3-010 B18

—NH—

3-011 B33

—NH—

3-012 B18

—O—

3-013 B23

—N(CH₃)—

TABLE 4 Compounds prepared according to the Examples wherein A is1-piperidinyl.

Co. Exp nr. nr. —V¹—M¹ —L— —R⁴ 4-001 B10 —CH₂ CH₂ CH₂CH₃ cb

4-002 B10 —CH₂ CH₂ CH₂CH₃ cb

4-003 B34* —CH₂ CH₂ CH₂CH₃ cb

4-004 B27 —CH₂ CH₂ CH₂CH₃ cb

4-005 B25 —CH₂ CH₂ CH₂CH₃ cb

4-006 B33 —CH₂ CH₂ CH₂CH₃ cb

4-007 B27 —CH₂ CH₂ CH₂CH₃ cb

4-008 B27 —CH₂ CH₂ CH₂CH₃ cb

4-009 B33 —CH₂ CH₂ CH₂CH₃ cb

4-010 B23 —CH₂—CH₂—CH(CH₃)₂ cb c —CF₃ 4-012 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-013 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-014 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-015 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-016 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-017 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-018 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-019 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-020 B22* —CH₂—CH₂—CH(CH₃)₂ cb

4-021 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-022 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-023 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-024 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-025 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-026 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-027 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-028 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-029 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-030 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-031 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-032 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-033 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-034 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-035 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-036 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-037 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-038 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-039 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-040 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-041 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-042 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-043 B23 —CH₂—CH₂—CH(CH₃)₂ cb

4-044 B23* —CH₂—CH₂—CH(CH₃)₂ cb

4-045 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-046 B33 —CH₂—CH₂—CH(CH₃)₂ cb

4-047 B33*

cb

4-048 B33

cb

4-049 B23

cb

4-050 B23

cb

4-051 B23

cb

4-052 B25

cb

4-053 B33

cb

4-054 B33

cb

4-055 B37

cb

4-056 B23

cb

4-057 B26

cb

4-058 B23

cb

4-059 B26

cb

4-060 B26

cb

4-061 B23

cb

4-062 B33

cb

4-063 B33

cb

4-064 B23

cb

4-065 B23

cb

4-066 B33

cb

TABLE 5 Other compounds prepared according to the Examples wherein A isa N-containing heterocycle

Co. Exp nr. nr. —V¹—M¹ —L— a-A-b —R⁴ 5-054 B47* —CH₂ CH₂ CH₂CH₃ cb

5-023 B1 —CH₂ CH₂ CH₂CH₃ cb

5-001 B11 —CH₂ CH₂ CH₂CH₃ cb

5-002 B1 —CH₂ CH₂ CH₂CH₃ cb

5-003 B23 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-004 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-005 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-006 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-007* B30 —CH₂—CH₂—CH(CH₃)₂ cb

5-008 B23 —CH₂—CH₂—CH(CH₃)₂ cb

5-009 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-053 B44* —CH₂—CH₂—CH(CH₃)₂ cb

5-052 B40* —CH₂—CH₂—CH(CH₃)₂ cb

— trifluoromethylsulfonic acid (salt form) 5-010 B1 —CH₂—CH₂—CH(CH₃)₂ cb

—O—CH₃ 5-011 B1 —CH₂—CH₂—CH(CH₃)₂ cb

—(CH₂)₃OH 5-012 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-013 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-014 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-015 B36* —CH₂—CH₂—CH(CH₃)₂ cb

5-016 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-017 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-018 B1 —CH₂—CH₂—CH(CH₃)₂ cb

—CH₃ 5-019 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-020 B32 —CH₂—CH₂—CH(CH₃)₂ cb

5-021 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-022 B1 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-024 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-025 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-026 B1 —CH₂—CH₂—CH(CH₃)₂ cb

—CH₃ 5-027 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-028 B1 —CH₂—CH₂—CH(CH₃)₂ cb

5-029 B23 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-030 B23 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-031 B23 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-032 B23 —CH₂—CH₂—CH(CH₃)₂ cb

5-033 B23 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-034 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-035 B33 —CH₂—CH₂—CH(CH₃)₂ cb

—OCH₃ 5-036 B33 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-037 B33 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-038 B33 —CH₂—CH₂—CH(CH₃)₂ cb

—F 5-039 B33 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-040 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-041 B33 —CH₂—CH₂—CH(CH₃)₂ cb

— 5-042 B33 —CH₂—CH₂—CH(CH₃)₂ cb

—Cl 5-043 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-044 B33 —CH₂—CH₂—CH(CH₃)₂ cb

5-045 B1 —CH₂—CH₂—CH(CH₃)₂ —OCH₂—

5-046 B29 —CH₂—CH₂—CH(CH₃)₂ —O(CH₂)₂—

—F 5-047 B1 —CH₂—CH₂—CH(CH₃)₂ —NH—

5-048 B33 —CH₂—CH₂—CH(CH₃)₂ —N(CH₃)—

5-049 B10

— 5-050 B33

cb

—N(CH₃)₂ 5-051 B1

cb

— a-A-b: a is the side with the R⁴ moiety; b is the side with the Lmoiety

TABLE 6 Compounds prepared according to the Examples wherein R² is nothydrogen.

Co. Exp. nr. nr. V¹ M¹ R² —L—A 6-001 B1 —CH₂—CH₂—CH(CH₃)—CH₂— —H —CH₃

C. Physico-Chemical DataLCMS-Methods:LCMS—General Procedure A

The HPLC gradient was supplied by a Alliance 2795XE comprising aquaternary pump with degasser, an autosampler, a column oven, a photodiode-array detector (PDA 2996) and a column as specified in therespective methods below. Flow from the column was split to a MSdetector. MS detectors were configured with electrospray ionizationsource. Nitrogen was used as the nebulizer gas. Mass spectra wereacquired from 50 to 600 in 0.5 seconds. The capillary needle voltage was3.5 kV and the source temperature was maintained at 140° C. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

LCMS—General Procedure B

The HPLC gradient was supplied by a HP 1100 from Agilent Technologiescomprising a pump (quaternary or binary) with degasser, an autosampler,a column oven, a diode-array detector (DAD) and a column as specified inthe respective methods below. Flow from the column was split to a MSdetector. The MS detector was configured with an electrospray ionizationsource. Nitrogen was used as the nebulizer gas. The source temperaturewas maintained at 140° C. Data acquisition was performed withMassLynx-Openlynx software.

LCMS—General Procedure C

The LC gradient was supplied by an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.) and diode-array detector (DAD). Flow from the column was splitto a MS detector. The MS detector was configured with an electrosprayionization source. Mass spectra were acquired by scanning from 100 to1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillaryneedle voltage was 3.5 kV and the source temperature was maintained at140° C. Nitrogen was used as the nebulizer gas. Data acquisition wasperformed with a Waters-Micromass MassLynx-Openlynx data system.

Method 1

In addition to general procedure A: Reversed phase HPLC was carried outon an Zorbax-C18 cartridge (3.5 μm, 4.6×50 mm) from AgilentTechnologies, with a flow rate of 1 ml/min. The column oven was set at25° C. Two mobile phases (mobile phase A: water+0.5% of formic acid;mobile phase B: acetonitrile+0.5% of formic acid) were used. First, 95%A and 5% B was hold for 0.1 minutes. Then a gradient was applied to 100%B at 5 minutes, kept till 6.0 minutes and equilibrated to initialconditions at 6.5 minutes until 7.0 minutes. Typical injection volumesof 5-20 μL were used. ES MS detector was used, acquiring both inpositive and negative ionization modes. Cone voltage was 30 V forpositive and 63 V for negative ionization mode.

Method 2

In addition to general procedure A: Reversed phase HPLC was carried outon an Zorbax-C18 cartridge (1.8 μm, 4.6×30 mm) from AgilentTechnologies, with a flow rate of 1.5 ml/min. The column oven was set at30° C. Two mobile phases (mobile phase A: water+0.05% of formic acid;mobile phase B: acetonitrile+0.05% of formic acid) were used. Thegradient conditions used are: 90% A and 10% B to 100% B at 3.5 minutes,kept till 3.7 minutes and equilibrated to initial conditions at 3.8minutes until 4.5 minutes. Typical injection volumes of 5-20 μL wereused. ES MS detector was used, acquiring both in positive and negativeionization modes. Cone voltage was 30 V for positive and 63 V fornegative ionization mode.

Method 3

In addition to general procedure B: Reversed phase HPLC was carried outon an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced ChromatographyTechnologies, with a flow rate of 1.5 ml/min, at 40° C. The gradientconditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B(acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to100% B at 7 minutes and equilibrated to initial conditions at 7.5minutes until 9.0 minutes. Injection volume 5 μl. High-resolution massspectra (Time of Flight, TOF) were acquired only in positive ionizationmode by scanning from 100 to 750 in 0.5 seconds using a dwell time of0.1 seconds. The capillary needle voltage was 2.5 kV for positiveionization mode and the cone voltage was 20 V. Leucine-Enkephaline wasthe standard substance used for the lock mass calibration.

Method 4

In addition to general procedure B: Same as Method 3, but using 10 μL ofinjection volume.

Method 5

In addition to general procedure B: Reversed phase HPLC was carried outon an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced ChromatographyTechnologies, with a flow rate of 1.5 ml/min, at 40° C. The gradientconditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B(acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to100% B at 7 minutes and equilibrated to initial conditions at 7.5minutes until 9.0 minutes. Injection volume 5 μl. Low-resolution massspectra (ZQ detector; quadrupole) were acquired by scanning from 100 to1000 in 1.0 second using a dwell time of 0.3 seconds. The capillaryneedle voltage was 3 kV. The cone voltage was 20 V and 50 V for positiveionization mode and 20 V for negative ionization mode.

Method 6

In addition to general procedure C: Reversed phase UPLC was carried outon a bridged ethylsiloxane/silica (BEH) C18 column (1.7 μm, 2.1×50 mm)with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 0.1%formic acid in H₂O/methanol 95/5; mobile phase B: methanol) were used torun a gradient condition from 95% A to 5% A, 95% B in 1.3 minutes andhold for 0.2 minutes. An injection volume of 0.5 μl was used. Conevoltage was 10 V for positive ionization mode and 20 V for negativeionization mode.

Method 7

In addition to general procedure B: Reversed phase HPLC was carried outon an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, at 60° C. witha flow rate of 1 ml/min, at 60° C. The gradient conditions used are: 90%A (0.5 g/l ammonium acetate solution), 5% B (acetonitrile), 5% C(methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes andequilibrated to initial conditions at 7.5 minutes until 9.0 minutes.Injection volume 2 μl. High-resolution mass spectra (Time of Flight,TOF) were acquired only in positive ionization mode by scanning from 100to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillaryneedle voltage was 2.5 kV and the cone voltage was 20 V.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Method 8

In addition to general procedure B: Reversed phase HPLC was carried outon a XDB-C18 cartridge (1.8 μm, 4.6×30 mm) from Agilent, with a flowrate of 1.5 ml/min, at 60° C. The gradient conditions used are: 80% A(0.5 g/l ammonium acetate solution), 20% B (mixture ofAcetonitrile/Methanol, 1/1) to 100% B in 6.5 minutes, kept till 7minutes and equilibrated to initial conditions at 7.5 minutes until 9.0minutes. Injection volume 5 μl. Low-resolution mass spectra (ZQdetector; quadrupole) were acquired by scanning from 100 to 1000 in 1.0second using a dwell time of 0.3 second. The capillary needle voltagewas 3 kV. The cone voltage was 20 V and 50 V for positive ionizationmode and 20 V for negative ionization mode.

Method 9

In addition to general procedure B: Reversed phase HPLC was carried outon an ACE-C18 column (3.0 μm, 4.6×30 mm) from Advanced ChromatographyTechnologies, with a flow rate of 1.5 ml/min, at 40° C. The gradientconditions used are: 80% A (0.5 g/l ammonium acetate solution), 10% B(acetonitrile), 10% C (methanol) to 50% B and 50% C in 6.5 minutes, to100% B at 7 minutes and equilibrated to initial conditions at 7.5minutes until 9.0 minutes. Injection volume 5 μl. High-resolution massspectra (Time of Flight, TOF) were acquired by scanning from 100 to 750in 0.5 seconds using a dwell time of 0.3 seconds. The capillary needlevoltage was 2.5 kV for positive ionization mode and 2.9 kV for negativeionization mode. The cone voltage was 20 V for both positive andnegative ionization modes. Leucine-Enkephaline was the standardsubstance used for the lock mass calibration.

Melting point determination was performed in open capillary tubes eitheron a Buchi B-540 or Mettler FP62.

TABLE 7 Physico-chemical data for the compounds. For salt forms, the[MH+] of the free base was reported. Co. Melting point RT LCMS Nr (° C.)[MH⁺] (min) Method Physical form 1-003 339 4.38 Method 3 White solid1-004 378 4.00 Method 3 White solid 1-005 413 4.54 Method 3 Pale yellowsolid 1-006 427 4.43 Method 8 Pale yellow solid 1-007 159 363 2.92Method 2 Light yellow solid 1-008 148 299 4.59 Method 1 White solid1-009 149 293 4.43 Method 3 Yellow solid 1-010 decomposes 336 5.00Method 5 Yellow solid 1-011  60 323 4.43 Method 3 Yellow solid 1-012decomposes 323 4.55 Method 3 Yellow solid 1-013 128 337 2.95 Method 2White solid 1-014 143 391 3.22 Method 2 Yellow solid 1-015 307 Method 1Solid 1-016 331 2.56 Method 2 Light yellow solid 1-017 331 2.60 Method 2Light brown solid 1-018 155 291 4.19 Method 1 Yellow solid 1-019 118 3074.45 Method 1 White solid 1-021 331 2.59 Method 2 Light yellow solid1-022 335 3.92 Method 3 Light brown solid 1-023 295 1.15 Method 6 Beigesolid 1-024 181 385 2.70 Method 2 Light yellow solid 1-025 397 4.92Method 3 Light brown solid 1-026 351 2.62 Method 2 White solid 1-027 3512.63 Method 2 Light yellow solid 1-028 180 327 4.54 Method 1 Pink solid1-030 153 371 2.76 Method 2 White solid 1-031 167 468 4.62 Method 3White solid 1-032 190 456 2.70 Method 2 Yellow solid 1-033  97 470 4.47Method 3 White solid 1-034 498 4.53 Method 8 White solid 1-035 136 4984.52 Method 8 White solid 1-036 498 5.19 Method 3 White solid 1-037 184500 4.47 Method 3 White solid 1-038 140 514 4.64 Method 3 White solid1-039 169 401 2.78 Method 2 White solid 1-040 180 429 2.47 Method 2White solid 1-041 155 463 3.17 Method 2 Beige solid 1-042 185 363 2.90Method 2 White solid 1-043 185 288 2.71 Method 1 Beige solid 1-044 141288 3.34 Method 1 White solid 1-045 160 288 2.81 Method 1 Solid 1-046185 362 3.96 Method 1 White solid 1-047 317 4.09 Method 3 Pale yellowsolid 1-048 188 347 4.20 Method 4 White solid 1-049 decomposes 409 5.13Method 3 White solid 1-050 135 245 3.85 Method 1 Yellow solid 1-051 3054.29 Method 1 Yellow solid 1-052 118 321 4.40 Method 1 Yellow solid1-053 decomposes 315 4.25 Method 3 White solid 1-055 123 337 2.73 Method2 White solid 1-056 195 352 3.64 Method 7 Bright yellow solid 1-057 136371 4.04 Method 3 White solid 1-058 122 336 4.72 Method 7 Yellow solid1-059 103 259 4.18 Method 1 Yellow solid 1-060 347 3.00 Method 3 Palebrown solid 1-061 346 3.93 Method 3 Pale yellow solid 1-062 346 3.61Method 7 White solid 1-063 102 374 4.16 Method 3 White solid 1-064 121360 3.97 Method 7 White solid 1-065 360 4.22 Method 7 White solid 1-066364 3.79 Method 3 White solid 1-067 414 4.68 Method 7 White solid 1-068decomposes 414 4.67 Method 7 Off white solid 1-069 414 4.40 Method 7 Offwhite solid 1-070 380 4.10 Method 7 Off white solid 1-071 371 3.86Method 7 White solid 1-072 371 3.90 Method 7 White solid 1-073 431 4.32Method 3 Off white solid 1-074 347 3.32 Method 7 White solid 1-075 3473.36 Method 7 White solid 1-076 347 3.55 Method 7 White solid 1-077 108259 3.92 Method 1 Beige solid 1-078 170 346 3.06 Method 8 White solid1-079 103 273 4.22 Method 1 White solid 1-080 149 267 4.45 Method 1White solid 1-081 257 4.13 Method 1 Yellow solid 1-082 123 273 4.29Method 1 Yellow solid 1-083 307 4.66 Method 4 Yellow solid 1-084 142 2674.25 Method 1 White solid 1-085 102 281 2.72 Method 2 White solid 1-086168 323 3.16 Method 2 Orange solid 1-087 125 285 3.97 Method 3 Paleyellow solid 1-088 161 285 4.09 Method 4 White solid 1-089 decomposes285 4.07 Method 3 White solid 1-090 123 301 2.74 Method 2 White solid1-091 137 301 2.76 Method 2 Yellow solid 1-092 423 5.01 Method 3 Whitesolid 1-093 172 343 3.05 Method 2 Off white solid 1-094 131 343 3.03Method 2 Light yellow solid 1-095  85 325 3.76 Method 1 White solid1-096 201 283 3.72 Method 1 Light brown solid 1-097 210 283 3.66 Method1 White solid 1-098 145 297 2.04 Method 2 White solid 1-099 327 3.35Method 3 Beige solid 1-100 297 4.11 Method 5 Yellow oil 1-101  96 2974.31 Method 1 White solid 1-102  99 270 4.07 Method 1 Light yellow solid1-103  91 311 4.22 Method 1 White solid 1-104 311 4.52 Method 3 Creamsolid 1-105 107 325 2.96 Method 2 Light orange solid 1-106 339 4.54Method 3 Pale yellow solid 1-107  67 311 2.51 Method 2 Light yellowsolid 1-108 313 3.51 Method 3 Cream solid 1-109 357 3.35 Method 3 Whitesolid 1-110  52 327 4.03 Method 3 Yellow solid 1-111 129 325 2.89 Method2 Light yellow solid 1-112 149 331 4.33 Method 7 White solid 1-113  65315 4.35 Method 1 White solid 1-114 133 315 4.30 Method 1 Yellow solid1-115 154 357 3.06 Method 2 White solid 1-116 333 2.69 Method 2 Whiteoil 1-117 166 359 5.21 Method 5 White solid 1-118 decomposes 339 3.68Method 3 White solid 1-119 decomposes 333 4.39 Method 5 Cream solid1-120 122 351 4.74 Method 3 Yellow solid 1-121 363 4.67 Method 3 Whitesolid 1-122 131 381 4.61 Method 3 White solid 1-123 189 399 4.92 Method3 White solid 1-124 385 5.88 Method 3 Pale yellow solid 1-125 355 4.00Method 3 White solid 1-126 decomposes 353 4.08 Method 5 Cream solid1-127 156 354 3.52 Method 1 White solid 1-128 107 368 2.05 Method 1White solid 1-129 384 3.23 Method 3 Cream solid 1-130 159 340 3.06Method 3 White Solid 1-131 132 322 2.42 Method 2 Pink solid 1-132 3363.98 Method 3 White solid 1-133 337 4.72 Method 7 White solid 1-134 294371 5.40 Method 3 Cream solid 1-135 351 5.33 Method 4 White solid 1-136397 4.64 Method 5 Cream solid 1-137 411 4.78 Method 3 White solid 1-138441 4.70 Method 3 Cream solid 1-139 396 3.95 Method 3 Pale brown solid1-140 359 5.13 Method 3 White solid 1-141 373 5.38 Method 3 White solid1-142 403 5.01 Method 3 White solid 1-143 118 389 3.07 Method 2 Whitesolid 1-144 100 403 3.03 Method 2 White solid 1-145 212 403 3.02 Method2 White solid 1-146 139 391 3.07 Method 2 White solid 1-147 146 391 3.07Method 2 White solid 1-148 173 391 3.06 Method 2 Yellow solid 1-149 120407 3.23 Method 2 White solid 1-150 177 407 3.18 Method 2 White solid1-151 154 398 2.89 Method 2 White solid 1-152 193 384 2.86 Method 2White solid 1-153 171 398 2.89 Method 2 Yellow solid 1-154 360 4.23Method 3 White solid 1-155 132 360 4.07 Method 7 Off white solid 1-156139 360 4.09 Method 3 Off white solid 1-157 162 374 4.36 Method 5 Whitesolid 1-158 142 374 4.23 Method 5 Cream solid 1-159 171 374 4.25 Method5 White solid 1-160 374 4.18 Method 3 Cream solid 1-161 378 4.17 Method3 White solid 1-162 156 392 4.21 Method 3 Pale brown solid 1-163 202 4422.94 Method 2 White solid 1-164 165 408 2.82 Method 2 White solid 1-165408 2.15 Method 2 White solid 1-166 404 4.05 Method 3 Cream solid 1-167404 4.05 Method 3 White solid 1-168 decomposes 364 3.27 Method 5Freeze-dried 1-169 144 3.94 2.62 Method 2 Beige solid 1-170 282 3.10Method 3 Yellow solid 1-171 189 296 3.97 Method 3 Bright yellow solid1-172 137 310 4.51 Method 1 Green solid 1-173 130 324 1.81 Method 2 Greysolid 1-174 340 4.02 Method 9 Yellow solid 1-175  75 324 3.54 Method 1Brown solid 1-176 198 324 3.55 Method 1 White solid 1-177 112 352 2.13Method 2 White solid 1-178 157 338 3.39 Method 1 Beige solid 1-179 144338 3.39 Method 1 White solid 1-180 Yellow solid 1-181 decomposes 3532.79 Method 3 Pale yellow solid 1-182 367 3.31 Method 3 Bright yellowsolid 1-183 354 5.04 Method 3 Pale yellow solid 1-184 368 3.30 Method 3White solid 1-185 384 4.45 Method 4 Yellow solid 1-186 269 321 3.47Method 3 Pale brown solid 1-187 322 4.52 Method 3 Yellow 1-188 364 5.66Method 3 Bright yellow solid 1-189 384 4.22 Method 3 Yellow solid 1-190384 4.21 Method 7 Yellow solid 1-191 decomposes 400 4.48 Method 7 Paleyellow solid 1-192 119 Bright yellow solid 1-193 358 5.21 Method 3 Brownsolid 1-194 372 5.17 Method 3 Yellow solid 1-195 372 5.35 Method 3Bright yellow oil 1-196 386 5.33 Method 3 Yellow solid 1-197 418 5.47Method 3 White solid 1-198 404 4.71 Method 3 White solid 1-199 136 3902.93 Method 2 Yellow solid 1-200 162 390 2.94 Method 2 Yellow solid1-201 342 3.35 Method 3 Cream solid 1-202 146 406 3.07 Method 2 Yellowsolid 1-203 173 402 2.90 Method 2 Yellow solid 1-204 157 397 2.75 Method2 Yellow solid 1-205 456 5.69 Method 3 Yellow solid 1-206 209 397 2.74Method 2 Yellow solid 1-207 379 2.68 Method 3 Yellow solid 1-208 3593.35 Method 7 Pale yellow solid 1-209 373 4.08 Method 3 Yellow solid1-210  73 373 4.01 Method 3 Yellow solid 1-211 142 401 4.53 Method 3Pale yellow solid 1-212 294 401 4.44 Method 3 Pale yellow solid 1-213 96 401 1.61 Method 2 White solid 1-214 326 4.26 Method 3 Brown solid1-215  70 360 3.70 Method 1 White solid 1-216 191 360 3.67 Method 1White solid 1-217 414 3.49 Method 7 Bright yellow solid 1-218 336 5.10Method 3 Yellow solid 1-219 350 5.32 Method 5 Bright yellow solid 1-220213 366 3.79 Method 3 Yellow solid 1-221 380 4.60 Method 4 Yellow solid1-222 352 4.17 Method 5 Yellow solid 1-223 171 352 4.09 Method 3 Yellowsolid 1-224 decomposes 368 3.67 Method 4 Yellow solid 1-225 151 382 4.08Method 3 Yellow solid 1-226 118 430 4.80 Method 3 Yellow solid 1-227 162380 4.79 Method 3 Yellow solid 1-228 148 400 5.19 Method 3 Bright yellowsolid 1-229 148 366 3.94 Method 3 White solid 1-230 143 393 3.98 Method3 Yellow solid 1-231 decomposes 393 3.68 Method 3 Yellow solid 1-232 3914.77 Method 3 Yellow solid 1-233 427 5.45 Method 4 Orange solid 1-234428 3.94 Method 3 Orange solid 1-235 151 333 3.57 Method 5 White solid1-236 decomposes 334 3.50 Method 5 Pale yellow solid 1-237 Yellow solid1-238 130 309 4.02 Method 1 Beige Solid 1-239 120 353 4.34 Method 1Yellow solid 1-240 169 339 3.73 Method 1 White solid 1-241 172 338 1.94Method 2 White solid 1-242 (oil) 325 2.54 Method 2 Black oil 1-243 166338 2.05 Method 2 Off white solid 1-244 122 352 2.10 Method 2 Whitesolid 1-245 135-140 414 2.62 Method 2 White solid 1-246 350 3.50 Method3 Cream solid 1-247 217 587 5.02 Method 8 White solid 1-248 347 3.44Method 3 White solid 1-249 350 3.68 Method 7 Yellow solid 1-250 334 3.89Method 3 White solid 1-251 117 309 4.09 Method 3 Off white solid 1-252120-121 311 4.24 Method 1 Beige solid 1-253 325 4.14 Method 3 Whitesolid 1-254 122 306 2.37 Method 2 White solid 1-255 233 494 2.78 Method2 Yellow solid 1-256 128 313 4.55 Method 1 Yellow solid 1-257 181 3453.69 Method 1 White solid 1-258 390 4.35 Method 4 Colourless oil 1-259323 4.62 Method 3 Pale grey solid 1-260 295 4.46 Method 4 White solid1-261 293 4.70 Method 3 Yellow solid 1-262 338 4.75 Method 3 White solid1-263 decomposes 338 4.83 Method 5 Creamy green solid 1-264 325 4.46Method 3 White solid 1-265  88 325 4.52 Method 5 White solid 1-266 3234.51 Method 3 Yellow solid 1-267 291 4.78 Method 3 Brown solid 1-268 3214.85 Method 3 Cream solid 1-269 334 5.24 Method 3 White solid 1-270 166334 5.24 Method 5 Orange solid 1-271 500 4.41 Method 3 White solid 1-272401 4.78 Method 3 White solid 1-273 347 4.15 Method 7 White solid 1-274decomposes 283 4.05 Method 3 White solid 1-275 174 297 4.10 Method 5White solid 1-276 311 4.33 Method 5 White 1-277 365 4.65 Method 3 Whitesolid 1-278 375 4.54 Method 3 White solid 1-279 116 381 4.69 Method 3White solid 1-280 327 4.18 Method 5 White solid 1-281  83 341 4.21Method 5 White solid 1-282 153 313 4.12 Method 3 White solid 1-283 3454.08 Method 3 Pale pink solid 1-284 190 363 4.32 Method 5 White solid1-285 200 381 4.83 Method 5 White solid 1-286 322 3.73 Method 3 Paleyellow solid 1-287 397 4.99 Method 3 Pale yellow solid 1-288 169 3234.30 Method 3 White solid 1-289 403 5.02 Method 3 Pale yellow 1-290 148445 5.24 Method 3 White solid 1-291 352 5.16 Method 3 Pale yellow solid1-292 154 396 3.82 Method 3 White solid 1-293 209 372 4.43 Method 3White solid 1-294 306 3.97 Method 3 White solid 1-295 359 3.31 Method 3Yellow solid 1-296 151 361 3.57 Method 7 Off white solid 1-297 350 4.78Method 7 Pale yellow solid 1-298 decomposes 282 3.97 Method 3 Creamsolid 1-299 296 4.00 Method 3 Pale brown oil 1-300 decomposes 367 3.91Method 3 White solid 1-301 decomposes 374 5.13 Method 3 Yellow solid1-302 375 4.01 Method 3 Yellow solid 1-303 310 4.14 Method 3 White solid1-304 322 4.51 Method 7 White solid 1-306 374 4.22 Method 7 2-001 183437 4.95 Method 3 Pale yellow solid 2-002 127 469 5.26 Method 3 Whitesolid 2-003 134 455 5.13 Method 3 Pale yellow solid 2-004 338 3.36Method 3 Pale yellow solid 2-005 367 4.07 Method 3 White solid 2-006 3794.08 Method 3 Pale yellow solid 2-007 369 3.76 Method 3 Off white solid2-008 382 3.45 Method 3 Pale yellow solid 2-009 424 3.34 Method 3 Paleyellow solid 2-010 112 469 5.21 Method 3 White solid 2-011 351 4.40Method 3 Yellow solid 2-012 365 4.44 Method 3 White solid 2-013 381 4.32Method 3 Pale yellow solid 2-014 433 5.04 Method 3 White solid 2-015decomposes 401 4.66 Method 3 Beige solid 2-016 409 4.33 Method 3 Whitesolid 2-017 379 4.55 Method 3 Pale brown solid 2-018 391 4.75 Method 3Pale yellow oil 2-019 413 4.49 Method 3 Yellow gum 2-020 463 5.05 Method3 Pale yellow solid 2-021 379 4.99 Method 3 Pale yellow solid 2-022 256483 5.49 Method 3 White solid 2-023 366 3.32 Method 3 Yellow gum 2-024352 3.83 Method 3 Yellow solid 2-025 366 4.17 Method 3 Yellow solid2-026 135 420 4.69 Method 3 White solid 2-027 377 3.72 Method 3 Offwhite solid 2-028 353 3.56 Method 3 Pale creamy solid 2-029 155 421 4.71Method 3 Pale brown solid 2-030 353 2.80 Method 3 Yellow solid 2-031 245387 3.38 Method 3 Yellow solid 2-032 383 3.40 Method 3 Yellow solid2-033 429 4.23 Method 3 Yellow gum 2-034 decomposes 417 3.89 Method 3Pale yellow solid 2-035 288 392 4.15 Method 3 White solid 2-036 159 3963.67 Method 3 Off white solid 2-037 223 White solid 2-038 140 435 4.73Method 3 White solid 2-039 125 467 5.05 Method 3 White solid 2-040 157Pale yellow solid 2-041 decomposes 365 3.38 Method 3 Pale brown solid2-042 decomposes 469 4.91 Method 3 White solid 2-043 110 483 4.97 Method3 Pale yellow solid 2-044 156 487 4.93 Method 4 White solid 2-045decomposes 519 5.47 Method 3 Pale yellow solid 2-046  92 497 3.96 Method8 Yellow solid 2-047 470 3.94 Method 3 Yellow solid 2-048 258 524 5.04Method 3 White solid 2-049 403 4.27 Method 4 Light brown solid 2-050 4214.39 Method 3 White solid 2-051 239 439 4.49 Method 3 White solid 2-052439 4.59 Method 3 White solid 2-053 415 4.48 Method 3 White solid 2-054429 4.42 Method 3 Yellow oil 2-055 390 3.59 Method 3 White solid 3-001124 338 3.57 Method 7 Pale yellow solid 3-002 White solid 3-003 125 3794.41 Method 3 White solid 3-004 188 434 4.90 Method 3 Off white solid3-005 393 4.47 Method 3 White solid 3-006 131 461 5.22 Method 3 Whitesolid 3-007 208 380 4.35 Method 3 White solid 3-008 448 5.10 Method 3Pale brown solid 3-009 117 462 5.20 Method 3 Off white solid 3-010 187White solid 3-011 decomposes 351 2.55 Method 3 White solid 3-012 4324.60 Method 3 Cream solid 3-013 211 497 4.95 Method 3 White solid 3-014432 5.35 Method 3 White solid 4-001 337 3.28 Method 3 White solid 4-002337 3.22 Method 7 White solid 4-003 132 351 3.33 Method 7 4-004 188 3533.20 Method 3 Cream solid 4-005 353 3.87 Method 3 Cream solid 4-006 3673.94 Method 7 White solid 4-007 367 3.51 Method 7 Pale yellow solid4-008 381 3.79 Method 7 White solid 4-009 377 3.91 Method 7 White solid4-010 342 4.19 Method 3 White solid 4-012 296 378 4.48 Method 3 Whitesolid 4-013 350 5.06 Method 3 White solid 4-014 decomposes 350 4.76Method 3 White solid 4-015 364 5.33 Method 3 Yellow oil 4-016 112 4185.09 Method 7 White solid 4-017 380 5.18 Method 3 White solid 4-018 3844.94 Method 3 White solid 4-019 100 412 5.18 Method 3 White solid 4-020448 5.43 Method 3 White gummy solid 4-021 decomposes 410 4.82 Method 3White solid 4-022 464 5.30 Method 3 White solid 4-023 365 4.43 Method 3Beige solid 4-025 283 447 4.63 Method 3 White solid 4-026 393 4.41Method 3 Brown solid 4-027 113 411 4.57 Method 3 White solid 4-028 4615.25 Method 3 White solid 4-029  91 461 5.28 Method 3 White solid 4-030425 5.09 Method 3 White foam 4-031 141 447 5.31 Method 3 White solid4-032 475 5.02 Method 3 4-033 475 5.03 Method 3 Yellow solid 4-034 253405 4.4 Method 3 Pale brown solid 4-035 389 4.93 Method 3 Pale yellowsolid 4-036 405 5.29 Method 3 Browm gummy oil 4-037  78 407 4.86 Method3 Yellow solid 4-038 214 391 4.35 Method 3 Beige solid 4-039 123 4085.09 Method 3 White solid 4-040 113 412 4.91 Method 3 Pale cream solid4-041 418 4.82 Method 3 Pale brown solid 4-042 decomposes 433 4.13Method 7 Yellow solid 4-043 138 379 4.64 Method 3 White solid 4-044 4354.53 Method 3 Pale yellow solid 4-045 380 4.93 Method 3 White solid4-046 282 414 3.73 Method 3 White solid 4-047 128 334 4.05 Method 7White solid 4-048 378 4.38 Method 7 Off white solid 4-049 138 497 4.89Method 3 White solid 4-050 decomposes 491 4.20 Method 3 White solid4-051 decomposes 509 4.88 Method 3 Pale brown solid 4-052 499 4.39Method 7 Pale brown solid 4-053 485 3.85 Method 7 Yellow solid 4-054Cream solid 4-055 155 435 3.85 Method 3 Cream solid 4-056 431 4.16Method 3 Cream solid 4-057 242 449 4.54 Method 3 Cream solid 4-058 4995.05 Method 3 White solid 4-059 157 475 5.27 Method 3 White solid 4-060 96 Off white solid 4-061 175 447 4.20 Method 3 Cream solid 4-062 139454 5.06 Method 3 White solid 4-063 471 3.56 Method 7 Off white solid4-064 159 443 4.43 Method 3 White solid 4-065 511 5.24 Method 3 Whitesolid 4-066 400 4.83 Method 3 White solid 5-001 decomposes 384 3.31Method 3 Off white solid 5-002   164.7 398 3.24 Method 3 White solid5-003 decomposes 322 4.33 Method 3 White solid 5-004 377 4.2 Method 3Pale cream gum 5-005  96 447 5.16 Method 3 White solid 5-006 100 3974.71 Method 3 White solid 5-007 350 4.75 Method 3 Colourless oil 5-008102 436 5.11 Method 3 White solid 5-009 473 4.97 Method 3 White solid5-010 118 298 2.37 Method 2 White solid 5-011 326 2.96 Method 3 Palebrown solid 5-012 257 2.72 Method 3 White solid 5-013 347 4.26 Method 3White solid 5-014 308 3.92 Method 5 Orange solid 5-015 350 3.75 Method 5Pale yellow solid 5-016 decomposes 306 3.93 Method 3 Pale brown solid5-017 decomposes 306 3.84 Method 3 Pale green solid 5-018 281 320 4.37Method 3 Pale yellow solid 5-019 382 5.31 Method 3 Pale yellow solid5-020 232 397 4.21 Method 3 Cream solid 5-021 decomposes 307 3.31 Method3 Syrup 5-022 307 2.93 Method 3 Beige solid 5-023 decomposes 384 3.51Method 3 Cream solid 5-024 284 398 3.53 Method 3 Cream solid 5-025 3983.72 Method 3 Cream solid 5-026 decomposes 338 4.43 Method 5 Brightyellow solid 5-027 decomposes 347 4.08 Method 7 White solid 5-028 3644.87 Method 3 White solid 5-029 234 307 3.89 Method 3 Pale yellow solid5-030 324 4.4 Method 3 Cream solid 5-031 134 322 4.72 Method 3 Yellowsolid 5-032 382 4.04 Method 3 White solid 5-033 376 5.35 Method 3 Whitesolid 5-034 421 4.44 Method 3 Pale cream solid 5-035 169 406 5.04 Method3 White solid 5-036 394 4.96 Method 3 White solid 5-037 217 380 4.57Method 3 Cream solid 5-038 141 Cream solid 5-039 276 361 4.52 Method 3White solid 5-040 111 393 4.87 Method 3 Cream solid 5-041 130 362 4.85Method 3 White solid 5-042 412 5.73 Method 3 Pale yellow 5-043decomposes 365 4.57 Method 3 Pale yellow solid 5-044 395 4.51 Method 3Brown gummy solid 5-045 378 4.06 Method 3 White solid 5-046 370 4.08Method 4 White solid 5-047 349 4.37 Method 3 White solid 5-048 441 5.22Method 3 Colourless oil 5-049 318 4.39 Method 3 Pale grey solid 5-050407 3.66 Method 3 White solid 5-051 166 410 2.63 Method 2 Grey solid6-001 175 341 5.54 Method 2 Beige solid decomposes = product decomposesin the course of the determination.D. Pharmacological Examples

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Thebehaviour of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 4.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding is a functional membrane-based assay used tostudy G-protein coupled receptor (GPCR) function whereby incorporationof a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein o subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGluR2 receptors are shown to be preferentially coupled toGαi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGluR2 receptors both inrecombinant cell lines and in tissues (Schaffhauser et al 2003,Pinkerton et al, 2004, Mutel et al (1998) Journal of Neurochemistry.71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33).Here we describe the use of the [³⁵S]GTPγS binding assay using membranesfrom cells transfected with the human mGluR2 receptor and adapted fromSchaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for thedetection of the positive allosteric modulation (PAM) properties of thecompounds of this invention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 hours, prior to washing in PBS, and then collection byscraping in homogenisation buffer (50 mM Tris-HCl buffer, pH 7.4, 4°C.). Cell lysates were homogenized briefly (15 s) using an ultra-turraxhomogenizer. The homogenate was centrifuged at 23 500×g for 10 minutesand the supernatant discarded. The pellet was resuspended in 5 mMTris-HCl, pH 7.4 and centrifuged again (30 000×g, 20 min, 4° C.). Thefinal pellet was resuspended in 50 mM HEPES, pH 7.4 and stored at −80°C. in appropriate aliquots before use. Protein concentration wasdetermined by the Bradford method (Bio-Rad, USA) with bovine serumalbumin as standard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulators in membranescontaining human mGluR2 was performed using frozen membranes that werethawed and briefly homogenised prior to pre-incubation in 96-wellmicroplates (15 μg/assay well, 30 minutes, 30° C.) in assay buffer (50mM HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 50 μM GDP, 10 μg/ml saponin,)with increasing concentrations of positive allosteric modulator (from0.3 nM to 50 μM) and either a minimal pre-determined concentration ofglutamate (PAM assay), or no added glutamate. For the PAM assay,membranes were pre-incubated with glutamate at EC₂₅ concentration, i.e.a concentration that gives 25% of the maximal response glutamate, and isin accordance to published data (Pin et al. (1999) Eur. J. Pharmacol.375:277-294). After addition of [³⁵S]GTPγS (0.1 nM, f.c.) to achieve atotal reaction volume of 200 μl, microplates were shaken briefly andfurther incubated to allow [³⁵S]GTPγS incorporation on activation (30minutes, 30° C.). The reaction was stopped by rapid vacuum filtrationover glass-fibre filter plates (Unifilter 96-well GF/B filter plates,Perkin-Elmer, Downers Grove, USA) microplate using a 96-well plate cellharvester (Filtermate, Perkin-Elmer, USA), and then by washing threetimes with 300 μl of ice-cold wash buffer (Na₂PO₄.2H₂O 10 mM,NaH₂PO₄.H₂O 10 mM, pH=7.4). Filters were then air-dried, and 40 μl ofliquid scintillation cocktail (Microscint-O) was added to each well, andmembrane-bound [³⁵S]GTPγS was measured in a 96-well scintillation platereader (Top-Count, Perkin-Elmer, USA). Non-specific [³⁵S]GTPγS bindingis determined in the presence of cold 10 μM GTP. Each curve wasperformed at least once using duplicate sample per data point and at 11concentrations.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention in the presence of added EC₂₅ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM), weregenerated using the Prism GraphPad software (Graph Pad Inc, San Diego,USA). The curves were fitted to a four-parameter logistic equation(Y=Bottom+(Top-Bottom)/(1+10^((Log EC₅₀−X)*Hill Slope) allowingdetermination of EC₅₀ values.

TABLE 8 Pharmacological data for compounds according to the invention.All compounds were tested in presence of mGluR2 agonist, glutamate at apredetermined EC₂₅ concentration, to determine positive allostericmodulation (GTPγS-PAM). Values shown are averages of duplicate values of11-concentration response curves, from at least one experiment. Allcompounds showed a pEC₅₀ value of more than 5.0, from 5.1 (weakactivity) to 7.6 (very high activity). The error of determination of apEC₅₀ value for a single experiment is estimated to be about 0.3log-units. GTPgS - hR2 PAM Co. Nr. pEC₅₀ 1-093 7.6 5-020 7.6 1-204 7.61-202 7.5 4-065 7.5 4-066 7.5 1-140 7.4 1-196 7.4 5-033 7.4 4-062 7.44-039 7.4 1-151 7.4 1-145 7.4 1-268 7.3 4-016 7.3 1-188 7.3 1-124 7.35-041 7.3 1-153 7.3 1-149 7.3 5-019 7.3 4-022 7.3 1-148 7.3 1-206 7.34-060 7.3 1-194 7.2 1-141 7.2 1-117 7.2 4-014 7.2 1-287 7.2 1-086 7.21-092 7.2 1-144 7.2 1-146 7.2 1-199 7.2 4-031 7.2 1-267 7.1 1-289 7.15-039 7.1 1-134 7.1 2-048 7.1 4-019 7.1 1-147 7.1 1-228 7.1 1-143 7.11-200 7.1 1-165 7.1 1-163 7.1 1-150 7.1 1-010 7.0 1-270 7.0 1-014 7.01-115 7.0 4-015 7.0 4-035 7.0 4-028 7.0 1-152 7.0 1-025 7.0 1-172 6.91-285 6.9 1-187 6.9 1-024 6.9 1-013 6.9 1-195 6.9 1-272 6.9 4-020 6.94-045 6.9 4-017 6.9 4-037 6.9 5-018 6.9 4-041 6.9 1-226 6.9 1-049 6.94-064 6.9 4-029 6.9 1-256 6.8 1-290 6.8 1-269 6.8 1-042 6.8 1-039 6.81-123 6.8 1-164 6.8 3-009 6.8 2-022 6.8 1-271 6.8 2-003 6.8 1-004 6.82-006 6.8 1-067 6.8 1-083 6.7 1-218 6.7 5-026 6.7 1-219 6.7 1-133 6.73-014 6.7 2-026 6.7 1-301 6.7 1-259 6.7 1-040 6.7 5-042 6.7 1-261 6.75-038 6.7 4-021 6.7 4-049 6.7 5-048 6.7 2-017 6.7 1-297 6.7 1-008 6.65-016 6.6 5-003 6.6 1-277 6.6 5-051 6.6 1-041 6.6 1-205 6.6 5-036 6.65-008 6.6 4-036 6.6 2-029 6.6 1-183 6.6 2-043 6.6 4-058 6.6 1-197 6.64-059 6.6 3-004 6.6 1-068 6.6 1-258 6.5 1-112 6.5 1-180 6.5 1-266 6.55-028 6.5 1-142 6.5 1-030 6.5 1-278 6.5 5-027 6.5 1-111 6.5 5-040 6.51-203 6.5 1-022 6.5 3-008 6.5 2-002 6.5 4-047 6.5 1-006 6.5 1-058 6.51-191 6.5 4-032 6.4 1-012 6.4 1-157 6.4 1-007 6.4 1-279 6.4 1-105 6.44-012 6.4 4-038 6.4 5-037 6.4 1-237 6.4 4-040 6.4 1-221 6.4 1-162 6.44-033 6.4 5-025 6.4 5-034 6.4 1-190 6.4 1-247 6.4 1-005 6.4 1-073 6.41-064 6.4 1-120 6.3 2-011 6.3 1-026 6.3 1-027 6.3 1-158 6.3 1-159 6.31-192 6.3 1-253 6.3 1-167 6.3 5-013 6.3 1-171 6.3 1-291 6.3 1-094 6.31-230 6.3 4-018 6.3 1-121 6.3 1-156 6.3 1-154 6.3 4-043 6.3 5-047 6.31-227 6.3 4-051 6.3 1-169 6.3 2-040 6.3 1-066 6.3 2-045 6.3 4-005 6.34-006 6.3 4-009 6.3 1-155 6.3 1-095 6.2 1-113 6.2 1-021 6.2 1-136 6.21-284 6.2 1-126 6.2 1-119 6.2 1-106 6.2 1-160 6.2 1-233 6.2 2-042 6.21-116 6.2 2-053 6.2 1-211 6.2 2-016 6.2 1-161 6.2 1-003 6.2 1-036 6.22-005 6.2 1-057 6.2 1-273 6.2 1-071 6.2 4-052 6.2 1-070 6.2 1-019 6.11-239 6.1 1-214 6.1 1-085 6.1 1-170 6.1 5-017 6.1 1-282 6.1 1-283 6.12-028 6.1 2-013 6.1 1-138 6.1 2-025 6.1 1-255 6.1 1-032 6.1 1-245 6.11-090 6.1 1-186 6.1 1-038 6.1 2-020 6.1 2-014 6.1 1-035 6.1 2-039 6.15-023 6.1 1-114 6.0 1-210 6.0 1-017 6.0 1-263 6.0 1-135 6.0 1-137 6.01-099 6.0 2-035 6.0 5-043 6.0 1-122 6.0 1-288 6.0 5-044 6.0 4-042 6.01-185 6.0 1-212 6.0 4-057 6.0 1-048 6.0 2-037 6.0 2-010 6.0 1-060 6.02-007 6.0 1-063 6.0 5-001 6.0 1-065 6.0 1-046 5.9 1-260 5.9 1-251 5.91-275 5.9 1-265 5.9 5-032 5.9 1-208 5.9 1-209 5.9 1-055 5.9 1-234 5.91-220 5.9 1-224 5.9 2-015 5.9 2-021 5.9 1-198 5.9 5-007 5.9 4-027 5.94-030 5.9 1-292 5.9 1-302 5.9 3-002 5.9 3-012 5.9 1-034 5.9 1-102 5.81-097 5.8 1-096 5.8 1-009 5.8 1-274 5.8 1-174 5.8 1-280 5.8 5-015 5.81-250 5.8 1-166 5.8 1-264 5.8 1-262 5.8 5-049 5.8 1-091 5.8 5-035 5.84-026 5.8 5-021 5.8 2-049 5.8 2-044 5.8 4-061 5.8 1-189 5.8 3-010 5.81-231 5.8 2-008 5.8 4-007 5.8 1-072 5.8 4-008 5.8 1-296 5.8 1-082 5.71-052 5.7 1-103 5.7 1-223 5.7 1-011 5.7 1-118 5.7 1-104 5.7 5-014 5.71-016 5.7 1-236 5.7 2-024 5.7 4-010 5.7 2-033 5.7 1-300 5.7 1-304 5.74-013 5.7 1-132 5.7 1-225 5.7 1-037 5.7 5-005 5.7 5-009 5.7 2-004 5.74-001 5.7 4-048 5.7 1-018 5.6 1-110 5.6 1-047 5.6 1-088 5.6 1-276 5.61-254 5.6 2-018 5.6 1-031 5.6 1-033 5.6 1-131 5.6 4-044 5.6 3-006 5.62-050 5.6 5-024 5.6 1-293 5.6 1-056 5.6 1-069 5.6 1-217 5.6 1-179 5.51-101 5.5 1-215 5.5 1-238 5.5 1-128 5.5 1-182 5.5 1-089 5.5 1-303 5.51-248 5.5 1-107 5.5 4-034 5.5 2-051 5.5 2-001 5.5 2-046 5.5 1-294 5.52-041 5.5 4-004 5.5 4-053 5.5 1-077 5.4 1-015 5.4 1-087 5.4 1-298 5.41-201 5.4 1-246 5.4 1-184 5.4 1-286 5.4 2-034 5.4 1-249 5.4 1-139 5.41-177 5.4 1-242 5.4 2-055 5.4 1-306 5.4 5-045 5.4 5-006 5.4 3-013 5.42-052 5.4 1-295 5.4 1-078 5.4 4-002 5.4 1-076 5.4 4-003 5.4 1-079 5.31-059 5.3 1-176 5.3 1-053 5.3 5-004 5.3 1-125 5.3 1-109 5.3 1-193 5.34-023 5.3 2-047 5.3 2-054 5.3 4-056 5.3 2-038 5.3 1-074 5.3 1-075 5.34-063 5.3 1-081 5.2 1-252 5.2 1-168 5.2 1-108 5.2 5-011 5.2 2-019 5.21-173 5.2 5-030 5.2 5-031 5.2 1-244 5.2 4-024 5.2 3-007 5.2 2-027 5.21-061 5.2 2-009 5.2 5-002 5.2 1-062 5.2 1-084 5.1 1-050 5.1 5-010 5.11-127 5.1 1-098 5.1 1-181 5.1 1-281 5.1 1-222 5.1 1-235 5.1 5-029 5.11-129 5.1 1-229 5.1 1-213 5.1 3-011 5.1E. Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa final compound of formula (I), the pharmaceutically acceptable acid orbase addition salts thereof, the stereochemically isomeric formsthereof, the N-oxide form thereof, a quaternary ammonium salt thereofand prodrugs thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

What is claimed:
 1. A method for treating, a central nervous systemdisorder in a human, wherein the central nervous system disorder is ananxiety disorder, a psychotic disorder selected from the groupconsisting of schizophrenia, schizoaffective disorder andschizophreniform disorder, or epilepsy or a convulsive disorder, themethod comprising administering to the mammal in need thereof a compoundof formula (I):

or a pharmaceutically acceptable salt or stereochemically isomeric formthereof, wherein V¹ is an unsubstituted bivalent saturated straight orbranched hydrocarbon radical having from 1 to 6 carbon atoms; M¹ ishydrogen; cycloC₃₋₇alkyl; phenyl optionally substituted with OCF₃ or F,phenyloxy; or tetrahydropyranyl; L is a covalent bond; —O—; —OCH₂—; or—NR⁷—; wherein R⁷ is hydrogen or an unsubstituted C₁₋₃alkyl; R² and R³are hydrogen; A is piperidinyl, of a form:

wherein n is 0, 1 or 2; R⁴ is, when present at any of b or c positions,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl; polyhaloC₁₋₃alkyl; Het³;Het³-C₁₋₆alkyl; Het³-oxy; Het³-oxy-C₁₋₆alkyl; Het³-C₁₋₆alkyloxy;—NR^(a)R^(b); or C₁₋₆ alkyl-NR^(a)R^(b); wherein R^(a) and R^(b) arehydrogen, C₁₋₆alkyl or C₃₋₇cycloalkyl; Het³ is pyridinyl; pyrimidinyl;pyridazinyl; pyrrolyl; indolyl; morpholinyl; oxadiazolyl; benzoxazolyl;benzofuranyl; indolinyl; 1,2,3,4-tetrahydro-isoquinolinyl; phthalazinyl;or benzo[1,3]dioxolyl; wherein each radical is optionally substitutedwith 1 or 2 substituents, each independently halo, C₁₋₆ alkyl, C₃₋₇cycloalkyl, polyhaloC₁₋₃ alkyl, cyano, mono(C₁₋₆alkyl)amino, oxo,phenyl, morpholinyl, or C₁₋₃alkyloxy.
 2. The method according to claim1, wherein V¹ is —CH₂—; —CH₂—CH₂—; —CH₂—CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂—;—CH₂—CH(CH₃)—CH₂—; —CH(CH₃)—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃)—CH₂—CH₂—; or—CH₂—CH₂—CH(CH₃)—CH₂—.
 3. The method according to claim 1, wherein V¹-M¹is —CH₂—CH₂—CH₂—CH₃; —CH₂—CH(CH₃)—CH₃; —CH(CH₃)—CH₂—CH₂—CH₃;—CH₂—CH(CH₃₋)CH₂—CH₃; or —CH₂—CH₂—CH(CH₃)—CH₃; or V¹ is —CH₂—;—CH₂—CH₂—; or —CH₂—CH₂—CH₂—; and M¹ is cyclopropyl; cyclopentyl;cyclohexyl; phenyl; or phenyloxy.
 4. The method according to claim 1,wherein: V¹ is —CH₂; —CH₂—CH₂—; —CH₂—CH₂—CH₂—; —CH₂—CH₂—CH₂—CH₂—;—CH₂—CH(CH₃)—CH₂—; —CH(CH₃)—CH₂—CH₂—CH₂—; —CH₂—CH(CH₃₋)CH₂—CH₂—; or—CH₂—CH₂—CH(CH₃)—CH₂—; M¹ is hydrogen; cycloC₃₋₇alkyl; phenyl; orphenyloxy; and Het³ is pyridinyl; pyrimidinyl; pyridazinyl; morpholinyl;oxadiazolyl; benzoxazolyl; benzofuranyl;1,2,3,4-tetrahydro-isoquinolinyl; indolyl; indolinyl; phthalazinyl; orbenzo[1,3]dioxolyl; wherein each radical is optionally substituted with1 or 2 substituents, each independently halo, oxo, C₁₋₆ alkyl,C₃₋₇cycloalkyl, polyhaloC₁₋₃alkyl, cyano, phenyl, morpholinyl,C₁₋₃alkyloxy; or mono(alkyl)amino.
 5. The method according to claim 1,wherein Het³ is pyridinyl; pyrimidinyl; morpholinyl, oxadiazolyl;benzofuranyl; indolinyl; or 1,2,3,4 tetrahydro isoquinolinyl; whereineach radical is optionally substituted with 1 or 2 substituents, eachindependently halo, C₁₋₆alkyl, polyhaloC₁₋₃ alkyl, oxo and phenyl. 6.The method according to claim 1, wherein the compound exists as opticalisomers, wherein said compound is either the racemic mixture or theindividual optical isomer.
 7. The method of claim 1, wherein the centralnervous system disorder is an anxiety disorder.
 8. The method of claim1, wherein the central nervous system disorder is an anxiety disorderthat is agoraphobia, generalized anxiety disorder (GAD),obsessive-compulsive disorder (OCD), panic disorder, or a posttraumaticstress disorder (PTSD).
 9. The method of claim 1, wherein the centralnervous system disorder is a psychotic disorder that is schizophrenia,schizoaffective disorder, or schizophreniform disorder.
 10. The methodof claim 1, wherein the central nervous system disorder is epilepsy or aconvulsive disorder that is generalized nonconvulsive epilepsy,generalized convulsive epilepsy, petit mal status epilepticus, grand malstatus epilepticus, partial epilepsy with or without impairment ofconsciousness, infantile spasms, epilepsy partialis continua, or otherform of epilepsy.
 11. The method of claim 7, wherein the central nervoussystem disorder is anxiety, schizophrenia, or epilepsy.
 12. The methodof claim 1, wherein an orthosteric agonist of mGluR2 is used incombination with a compound of formula (I).
 13. The method of claim 1,wherein the compound has a mGluR2 positive allosteric modulation EC₅₀ ofabout 1 μM or less.
 14. The method of claim 1, wherein the compound offormula (I) is: